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REVIEW ARTICLE
From the Departments of Internal Medicine and Molecular
Virology, Immunology, and Medical Genetics, Divisions of
Hematology/Oncology and Human Cancer Genetics, and the Comprehensive
Cancer Center, The Ohio State University, Columbus, OH.
Since the cloning of interleukin (IL)-15 six years ago,
there have been numerous studies examining the molecular and cellular biology of this cytokine. IL-15 and IL-2 have similar biologic properties in vitro, consistent with their shared receptor (R) signaling components (IL-2/15R The discovery of IL-15 and its relation to IL-2
Scientists at the Immunex Corporation (Seattle, WA) isolated the 14- to 15-kd protein responsible for the CTLL proliferation within CV-1/EBNA supernatants using anion-exchange and high-pressure liquid chromatography and sequenced the NH2-terminal residues. Degenerate oligonucleotide primers were generated from this partial protein sequence and were used to obtain the full-length simian IL-15 cDNA from a CV-1/EBNA cDNA library. With simian IL-15 cDNA as a probe, the full-length human IL-15 cDNA was cloned from the IMTLH bone marrow stromal cell line.1 The IL-T protein identified by researchers at the National Institutes of Health within HuT-102 supernatants was later cloned and shown to be a chimera composed of the HTLV-1 long terminal repeat (LTR) and human IL-15. The HTLV-1 LTR was fused in frame immediately upstream of IL-15, thereby deleting a portion of its 5' untranslated region (UTR).2-4 Because IL-15 was initially identified through its ability to mimic
IL-2-induced T-cell proliferation, the biochemical and functional
relation between these cytokines was quickly examined. Comparisons of
the primary protein and cDNA sequences of human or simian IL-15 yielded
little primary homology to IL-2; however, computer modeling of IL-15's
secondary structure suggested that IL-15 belonged to the 4 Structure of the genomic locus encoding IL-15 The IL-15 gene spans 34 kb or more, mapping to human chromosome 4q31 and the central region of mouse chromosome 8.10,11 The genomic structure of human IL-15 contains 9 exons (7 coding exons), with a similar intron/exon structure and estimated size between the murine and human IL-15 genes.10,11 More recently, an alternative exon has been described in human12-14 and murine15,16 IL-15, consisting of an additional sequence between exons 4 and 5 that encodes an alternative leader peptide. The structure of the human IL-15 genomic locus is diagramed in Figure 1 and includes the recently described alternative exon (4A).11,12,14 The IL-2 gene is located on human chromosome 4q26-28 and consists of 4 exons and 3 introns.17,18 Of note, the overall intron/exon structure of the portion of the IL-15 gene encoding the mature IL-15 protein (4 exons and 3 introns) is similar to that of the IL-2 gene and other 4 -helix bundle
cytokines.5 However, consistent with other family members,
there is little primary homology between IL-2 and IL-15 at the
nucleotide or protein level (Figure
2).1 Thus, although it is
doubtful that the IL-2 and IL-15 genes have a direct, recent ancestral
relationship, the gene structure of all members of the 4 -helix
bundle cytokine family appears similar.5
IL-15 mRNA isoforms, signal sequences, and intracellular trafficking The originally identified human IL-15 cDNA contains a 5' UTR of at least 316 base pairs (bp), a 486-bp open reading frame, and a 3' UTR of at least 400 bp, encoding a precursor IL-15 with an unusually long 48-amino acid (AA) leader peptide and a 114-AA mature protein.1 Identification of human, simian, and murine IL-15 indicated that IL-15 was conserved between species (97% identity comparing human and simian; 73% identity comparing human with murine).1 An alternative human IL-15 cDNA was identified containing an additional exon.12,13 This variant IL-15 human cDNA contains 119 nucleotides (nt) within intron 4 but lacks exons 1 and 2 of the original cDNA, resulting in a smaller spliced mRNA product (Figure 1).14 However, this exonic sequence encoded 3 premature stop codons and a novel downstream ATG translation start site, resulting ultimately in an IL-15 precursor protein with a 21-AA short signal peptide (SSP), compared with the original 48-AA long signal peptide (LSP). A similar alternative transcript has been described in the mouse.15,16 In human and mouse, both IL-15 isoforms encode an identical mature IL-15 protein, containing differences only within the signal sequence. Regulation of the IL-15 mRNA species expressed may occur through alternative splicing and/or an additional uncharacterized IL-15 promoter driving the expression of the SSP-IL-15.14The 2 IL-15 mRNA isoforms have significant differences in the
N-terminal portions of their leader peptides (Figure 1). Leader peptides determine the intracellular localization and potential secretion of the associated mature protein. Both LSP-IL-15 and SSP-IL-15 appear to have low secretion potential compared with well-secreted cytokines such as IL-2, as replacement of either endogenous IL-15 signal peptide (SP) by CD3313 or
IgV Structure of the mature IL-15 protein The 14- to 15-kd, 114-AA mature IL-15 protein is encoded by exons 5 to 8 of the IL-15 gene (Figure 1).1,10,11 IL-15 contains 2 disulfide bonds at positions C42-C88 and C35-C85 (single-letter amino acid codes), the former being homologous to the C-C within IL-2. There are 2 N-linked glycosylation sites at the C-terminus of the IL-15 protein, at N79 and N112. The mature IL-15 protein has been predicted to have strong helical moments at AAs 1 to 15, 18 to 57, 65 to 78, and 97 to 114, supporting a theoretical model of a 4-helix bundle
structure (Figure 2).1,23
The IL-15 receptor (R) complex and its relation to the IL-2R complex Three different IL-2R complexes exist: The isolated IL-2R binds
IL-2 with low affinity (Ka approximately 108
M 1) without transducing a signal; the heterodimeric
IL-2R  binds IL-2 with intermediate affinity (Ka
approximately 109 M1) and transduces
intracellular signals; and the heterotrimeric IL-2R binds IL-2
with high affinity (Ka approximately 1011 M1) and also signals.18,24,25 The IL-2R,
also referred to as c, is shared by receptors for IL-2,
IL-4, IL-7, IL-9, and IL-15.26,27 Early experiments using
specific blocking monoclonal antibodies (MoAbs) documented the
participation of the IL-2R and c, but not the
IL-2R, in IL-15 binding and function, suggesting the presence of an
additional subunit for high-affinity IL-15 binding to the IL-15R
complex.3,7,28,29 The murine and human IL-15R subunits
were subsequently cloned and characterized and shown to be highly
homologous to their IL-2R counterparts.29,30 The
full-length human IL-15R is a type-1 transmembrane protein with a
signal peptide of 32 AAs, an extracellular domain of 173 AAs, a
transmembrane domain of 21 AAs, a 37-AA cytoplasmic tail, and multiple
N- or O-linked glycosylation sites.30,31 Comparison of the
IL-2R and the IL-15R revealed the presence of a conserved protein
binding motif (sushi domain or GP-1 motif) and similar intron/exon
structure, placing IL-2R and IL-15R as the founding members of a
new receptor family.29 Through transfection experiments, it was established that the full-length IL-15R alone was sufficient for high-affinity (Ka greater than or equal to
1011 M1) binding of IL-15, but, similar to
IL-2R, it played no role in signal transduction. This high affinity
of the isolated IL-15R for IL-15 is in stark contrast to the
IL-2R, which has low affinity for IL-2 (Ka approximately
108 M1) in the absence of the IL-2R.
Thus, the IL-15R binds IL-15 with high affinity, but transduces
signals only in the presence of the IL-2/15R and c
(Figure 2). IL-15, like IL-2, may also bind and signal through the
heterodimeric IL-2/15Rc with intermediate affinity
(Ka approximately 109 M1) in the
absence of IL-15R.28
Eight splicing variants of the hIL-15R The originally identified full-length IL-15R How does IL-15 relate to other cytokines that use the
c receptor, including
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which use additional
subunit(s) for specificity or signaling.34,35 In vivo
experiments engineering mice with targeted disruption of these
cytokines or their specific receptor subunits elegantly demonstrated
that although c is shared, it mediates different
biologic functions when paired with individual cytokines. Comprehensive
comparative reviews of c-binding cytokines have been
provided elsewhere.36-38
Pathways of IL-15 signal transduction Because IL-2 and IL-15 share common signaling components (IL-2/15Rc), most evidence to date suggests that the
interaction of IL-15 with its receptor complex in various cell types
leads to a series of signaling events that are similar, if not
identical, to those elicited by IL-2.39 These include
activation of the Janus kinase (Jak)/signal transducer and activator of
transcription (STAT) pathway.40 IL-2/15R is associated
with Jak1 and the c is associated with Jak3, resulting
in STAT3 and STAT5 phosphorylation, respectively, after ligation with
IL-15 (Figure 2).41,42 Additional signaling pathways
through the IL-2/15R complexes include the src-related
tyrosine kinases, induction of Bcl-2, and stimulation of the
Ras/Raf/MAPK pathway that ultimately results in fos/jun activation.43 In neutrophils, IL-15 has been shown to
activate NF- B but not AP-1, whereas IL-15 stimulation of bulk human
peripheral blood lymphocytes activated both transcription
factors.44 However, reports of IL-15- but not
IL-2-induced signals in an IL-15R+IL-2/15R colonic
epithelial cell line leave open the possibility of alternative
IL-15R signaling mechanisms.45 The alternative receptor
system in mast cells (IL-15RX) has been shown to induce phosphorylation
of Jak2 and STAT5,33,46 as well as Tyk2 and STAT6.47
Physiologic expression of IL-15 IL-15 mRNA is produced by multiple tissues (placenta, skeletal muscle, kidney, lung, heart, monocytes/macrophages)1 and numerous cell types through various stimulatory conditions.48-60 The first cell types to be implicated as a functionally relevant source of IL-15 in the context of the immune response were members of the monocyte/macrophage lineage.48,49 Other antigen-presenting cells (APCs), such as blood-derived dendritic cells, have been shown to produce IL-15 mRNA and protein, suggesting a role in the attraction and stimulation of T cells.50,51 IL-15 is also produced by bone marrow (BM) stromal cell lines,1 primary human BM stromal cells,52 thymic epithelium,53 and fetal intestinal epithelium,54 consistent with IL-15's role during hematopoiesis. Epithelial and fibroblast cells from various tissues have been documented to produce IL-15 mRNA and/or protein, including kidney epithelial cell lines,1 epidermal skin cells and keratinocytes,55 fetal skin,56 retinal pigment epithelium,57 and intestinal epithelial cells.58 Other cells producing IL-15 with a less obvious function, and requiring further investigation, include kidney proximal tubule cells59 as well as astrocytes and microglia.60 Although not detected initially,1 T cells were later shown by more sensitive techniques to express IL-15 mRNA.61 Considering the extensive posttranscriptional control of IL-15 now evident (see below), it will be important to document IL-15 protein production, either intracellularly, at the cell surface, or secreted extracellularly, to better understand the true role of IL-15 during normal homeostasis and immune defense.Regulation of IL-15 gene expression IL-15 transcription, translation, and secretion have proved to be regulated through multiple complex mechanisms. This topic has been recently reviewed in depth elsewhere,46,62 and only the major points of interest are summarized here. Although transcriptional control of IL-15 is important,63,64 the principle level of IL-15 regulation appears to be posttranscriptional.Control of transcription.
Both human and murine 5' regulatory regions upstream of exon 1 have
been cloned, sequenced, and analyzed for consensus transcription factor
binding motifs.61,65 These studies revealed some common consensus binding sites within the mouse and human promoter regions, including  348 to 336 relative to the cap site of the
murine IL-15 promoter, following the observation that IRF-1/ mice simultaneously lack inducible IL-15
expression and natural killer (NK) cells.63,64 It remains
unclear what upstream signals are responsible for IRF-induced IL-15
expression during the normal physiologic process of NK cell development
in the BM (discussed below).
Primary regulation of IL-15: translation, intracellular trafficking, and secretion. Three primary checkpoints have been identified that regulate IL-15 mRNA translation into the IL-15 precursor protein: multiple start codons (AUGs) in the 5' UTR, the unusual LSP and SSP, and a negative regulator near the C-terminus of the precursor proteins. The LSP-IL-15 5' UTR is relatively long (more than 316 nt in humans) and contains multiple (12 in humans) AUGs upstream of the actual translation start site that have been shown to dramatically reduce translational efficiency.1,4,66 Bamford et al4 demonstrated that removal of 8 of 10 upstream AUGs in the 5' UTR of the human LSP-IL-15 by fusion with the HTLV-1R region resulted in enhanced IL-15 protein production in the HuT-102 cell line (approximately 5- to 10-fold). However, when the upstream AUGs were circumvented, IL-15 translation and secretion still appeared lower than those of other cytokines, such as IL-2. Tagaya et al14 showed that replacement of endogenous IL-15 signal peptides with the human IL-2 signal peptide resulted in dramatically elevated IL-15 levels detectable in supernatants from COS-7 transfectants. LSP-IL-15 was shown to have a lower translational efficiency than SSP-IL-15 or IL-2SP-IL-15. With the use of IL-15-GFP fusion constructs, it was evident that SSP-IL-15 was restricted to the cytoplasm and nucleus, whereas LSP-IL-15 was detected within the ER/Golgi apparatus. Thus, it appears that SSP-IL-15 is translated efficiently but not secreted, whereas LSP-IL-15 is translated less efficiently but has complex trafficking through the ER/Golgi pathway and is secreted from the cell at low levels.14,21 Similarly, Gaggero et al20 showed that LSP-IL-15 and exogenous IL-15 were detectable in Chinese hamster ovary (CHO) cell endosomes, indicating that rapid uptake by IL-15R-bearing cells may have a regulatory effect on the action of IL-15. The CTLL bioactivity of the LSP-IL-15-GFP construct was significantly higher than that of the LSP-IL-15 without a 3' tag, suggesting that a signal in the carboxyl portion of the mature IL-15 protein results in inefficient secretion, possibly through a retention signal.20 Through the systematic elimination of these 3 checkpoints, that is, removing upstream AUGs, replacing the endogenous human IL-15 leader with that of IL-2, and fusing the C-terminus of the IL-15 mature protein with the FLAG epitope tag, the synthesis of bioactive IL-15 increased 250-fold.67 Such complex and tight control of the IL-15 gene product is unusual for most cytokines characterized thus far and may indicate that IL-15, if overproduced, is somehow dangerous to the host. Transgenic mice that overexpress IL-15 as a result of elimination of posttranscriptional checkpoints recently provided in vivo evidence supporting this hypothesis.68 These mice developed a fatal lymphocytic leukemia following early expansions in NK and CD8+ T cells (see below). Recently, Musso et al69 detected bioactive IL-15 protein constitutively expressed on the surface of human monocyte/macrophage cell lines and primary human monocytes. Cell surface expression was increased upon stimulation with interferon (IFN)-, suggesting a
mechanism by which IL-15 could exert a biologic effect while being
undetectable in culture supernatants. It is unclear whether this
membrane expression of IL-15 depends upon signal peptide expression.
Another recent report demonstrated constitutive IL-15 protein
expression in human PBMCs by Western analysis and flow cytometry, which
was up-regulated by Cryptococcus neoformans, LPS, or
IFN-.70 Further study should reveal the exact cell types, tissue distribution, and functional significance of constitutive cell surface expression of IL-15. IL-15's function in promoting the
survival of IL-15-responsive cell types, such as NK
cells71 and memory T cells,72 may be one
hypothesis explaining the reason for low constitutive protein
expression. Then, in response to an infectious insult, cytoplasmic
protein may be translocated to the cell surface to further stimulate
IL-15R-bearing cells, in combination with additionally induced
monokines such as IL-12.
In other physiologic settings such as NK cell development (discussed
below), it will be interesting to examine BM stromal cells for
constitutive cell-surface expression of IL-15 and to test whether any
signals induce the movement of cytoplasmic IL-15 protein to the cell
surface. In both of these settings, it seems likely that activation of
monocytes/macrophages (and other cells such as dendritic cells and
epithelium) or appropriate stimulation of BM stromal cells could result
in more efficient IL-15 synthesis, translocation, and secretion through
removal of the multiple posttranscriptional control points.
An essential role for IL-15 in NK cell development Two critical features of the mammalian innate immune system are its ability to rapidly limit the spread of infectious pathogens and its ability to prepare the antigen-specific or adaptive immune system to effectively clear the pathogens.73 NK cells74,75 are large granular lymphocytes (LGLs) that demonstrate cytotoxicity against tumor and virally infected cells, produce immunoregulatory cytokines and chemokines, and are an important component of the innate immune defense against viruses, fungi, bacteria, and protozoa.76-80 NK cells also express a number of cell surface receptors that recognize MHC class I ligands and regulate NK cell activation and lysis of target cells,81,82 and are likely to be important for the control of some cancers.83It has long been appreciated that NK cells require the BM
microenvironment for complete maturation, based upon studies examining mice with BM ablation by strontium 89 or
IL-15 differentiates human NK cells in vitro.
First, for IL-15 to be the major physiologic growth factor responsible
for NK cell ontogeny, it must be expressed at the anatomic site of NK
cell differentiation, the BM. In support of this, the human IL-15 cDNA
was first cloned from the IMTLH BM stromal cell line.1
Mrozek et al52 directly demonstrated that primary human BM
stromal cells produced IL-15 at the transcript and protein levels,
while lacking any expression of IL-2. Further, a 3-week culture of
CD34+ hematopoietic progenitor cells (HPCs) supplemented
with rIL-15 induced the differentiation of functional CD56+
NK cells in the absence of stroma or other cytokines. The
CD56+ NK cells generated in these cultures lysed MHC class
I tumor targets, produced cytokine and chemokines upon stimulation, and expressed cytoplasmic CD3- + cells after 10 days, and
cell sorting experiments showed that these
CD34brightIL-2/15R+ cells have a 65- to
200-fold higher NK cell precursor frequency compared with freshly
isolated CD34+ HPCs. FL and KL also increased expression of
IL-15R mRNA within CD34+ HPCs measured by reverse
transcriptase polymerase chain reaction (RT-PCR). Thus, human NK cell
development can be divided into an early phase in which an NK
progenitor cell responds to early-acting stromal cell growth factors
(eg, FL or KL) and develops into an NK cell precursor intermediate with
the basic phenotype
CD34brightIL-2/15R+CD56. This
NK precursor is then responsive to IL-15 for maturation into a
functional CD56+ NK cell (Figure
3).106
It is important to note that the NK cells resulting from adult CD34+ HPCs in stroma-free cultures with IL-15 are CD56+, lyse tumor target cells, and produce immunoregulatory cytokines and chemokines upon stimulation. However, these NK cells have high-density expression of CD56, closely resembling the minor CD56bright NK cell population in peripheral blood, as they have little surface expression of CD16, with most cells expressing C-type lectin CD94/NKG2 NK receptors (NKR) and only small (1% to 8%) percentages of cells expressing killer-cell immunoglobulin-like receptor (KIR).106 This suggests that other soluble or cell-contact signals, perhaps from BM stroma, are required for normal KIR acquisition and other CD56dim NK characteristics, or alternatively the CD56dim NK cell may have a different precursor. To address these issues, further experiments are needed comparing IL-15-based culture systems using various starting HPC populations, with and without autologous BM stroma (or other MHC class I interaction systems). Additional human culture systems have also supported a central role for IL-15 in human NK cell development from various starting progenitor populations, including cord blood CD34+,107,108 adult BM CD34+,108 fetal liver CD34+CD38±,109 and thymocyte T/NK progenitors.110 Beginning with CD56 CD16+ cord blood cells, Gaddy and
Broxmeyer111 have demonstrated that IL-15 induced the
maturation of these cells into highly lytic, phenotypically mature NK
cells. Collectively, these in vitro human culture systems demonstrate a
central role for IL-15 in the later stages of NK cell development from
various adult and fetal progenitors. Further studies are needed to
clarify how IL-15 acts in concert with signals from early-acting growth
factors and stromal cells to facilitate physiologic human NK cell
development and normal NK cell repertoire acquisition. The basic
understanding of how human NK cells develop can also be directly
translated to optimizing the ex vivo112 and in vivo
expansion of this lymphocyte subset for therapeutic intervention.
IL-15 differentiates murine NK cells.
In vitro murine culture systems have also demonstrated a critical role
for IL-15 during NK cell ontogeny. Leclercq et al showed that
bipotential T/NK progenitors113 isolated from the thymus selectively differentiated into NK cells in the presence of
IL-15.53 Addition of high concentrations of IL-15 to
progenitors in fetal thymic organ cultures (FTOCs) blocked TCR and respond to IL-15 for mature NK cell development. In both systems, there is
abnormal NK receptor repertoire development in the presence of IL-15
alone, suggesting that other signals, as discussed earlier, are
required for proper NKR acquisition.
Mice with targeted genetic alterations demonstrate that IL-15 is a
critical NK cell differentiation factor in vivo.
As introduced earlier, the phenotypes of mice with targeted disruption
of IL-2, IL-2R / mice develop into functional NK cells upon
culture in IL-15 or transfer into lethally irradiated wild-type mice,
suggesting that IRF-1 is required for the expression of IL-15 in the BM
microenvironment. Indeed, IRF-1-binding sites have been identified in
the 5' regulatory region of the IL-15 gene, supporting this
hypothesis.63 At present, it is unclear what provides the
endogenous signal to activate IRF-1 within BM stromal cells, which in
turn induces the IL-15 expression important for NK cell development.
Mice with targeted disruption of the Ets-1 transcription factor were
shown to have a selective deficit of NK cells.124
Ets-1/ mice do not appear to have defects in
IL-15R, IL-15, or IL-2 expression, leaving the precise
mechanism responsible for this NK cell deficiency unknown. Because
Ets-1 is expressed in mature NK cells, it is possible that upstream
IL-15-derived signals may induce Ets-1 that may then orchestrate the
expression of an NK cell genetic program. Further investigation into
the genetic changes at the molecular level during NK cell
differentiation will help to clarify the gene programs activated during
NK cell ontogeny and the transcription factors involved in this process.
Lodolce et al9 recently generated mice with targeted
disruption of the IL-15R, providing direct evidence that the
IL-15/IL-15R system is critical for murine NK cell
development. These mice contain multiple defects in innate immune
effectors, including an absence of splenic NK cells and NK cytotoxic
activity. Moreover, IL-15/ mice also lack any
phenotypic or functional NK cells in the spleen and liver, a defect
that is reversible upon administration of exogenous IL-15 for 1 week.8 Exogenous IL-15 treatment of normal mice increases
NK cell activity and both the percentage and absolute number of splenic
NK cells.8,125,126 Transgenic mice that overexpress murine
IL-15 have been generated and demonstrate a striking early expansion in
NK cells.68 Thus, in vivo evidence demonstrates that IL-15
is requisite for murine NK cell development, and exogenous IL-15
supports the differentiation of human NK cells in BM culture systems.
These basic observations provide invaluable insight into the critical,
nonredundant role of IL-15 during NK cell development and suggest the
potential utility of IL-15 therapy to expand NK cells in patients.
IL-15 activates NK cell proliferation, cytotoxicity, and cytokine production and regulates NK cell/macrophage interaction NK cells constitutively express cytokine receptors and produce abundant cytokines and chemokines during the early, innate immune response to infection. Such NK cell-derived immunoregulatory factors may be vital in the orchestration of the innate immune response, as well as influence the developing adaptive response.73,78,127 NK cells constitutively express IL-2/15Rc, but the lack of abundant IL-2 during the
early innate immune response prompted us to investigate the role of
IL-15 as the more important physiologic ligand for NK cell
proliferation, cytotoxicity, and cytokine production in this setting.
The majority (approximately 90%) of human NK cells have low-density
surface expression of CD56 (CD56dim), express high surface
density of CD16 (FcRIII), and have a low proliferative capacity.
CD56bright NK cells represent a minor subset (approximately
10%) of human NK cells that are low or negative for CD16 and are
capable of high proliferation.75
NK cell proliferation and cytotoxicity.
IL-15 induced the proliferation of CD56bright NK cells in a
dose-dependent fashion to a similar extent as IL-2, yet required a
nanomolar concentration to activate the IL-2/15R IL-15 costimulates NK cell cytokine and chemokine production and
regulates interactions between macrophages and NK cells.
IL-15 acts in concert with IL-12 to induce the macrophage-activating
factors IFN- , mycobacteria, Toxoplasma
gondii, C neoformans, and Salmonella have been shown to
express IL-15.1,48,49,134,135 In human cocultures of
LPS-stimulated macrophages and NK cells, endogenous IL-15 produced by
the activated macrophages, working in concert with IL-12, was shown to
be critical for optimal IFN- production by human NK
cells.48 Similarly, in vitro culture of LPS-activated
severe combined immunodeficiency (SCID) mouse splenocytes (NK cells and
macrophages) produced abundant IFN- protein, which was abrogated by
blocking the IL-2/15R or neutralizing IL-15.133 In
vivo, preadministration of either an antibody that blocks the
IL-2/15R or a neutralizing anti-IL-15 antiserum to SCID mice
resulted in a significant reduction in serum IFN- measured in vivo 6 hours after an LPS challenge.133 Therefore, in both mice
and humans, activated macrophages and NK cells interact through a
paracrine feedback loop, with macrophages producing monokines (eg,
IL-15 and IL-12) that bind to surface receptors constitutively present
on NK cells, resulting in the production of macrophage-activating
factors (eg, IFN-). NK cell-derived macrophage-activating factors
in turn feed back upon the macrophages to further augment their
activation (Figure 4). Thus,
macrophage-derived IL-15 contributes with other monokines (especially
IL-12) to the proinflammatory cascade leading to innate immune IFN-
production. Additionally, Ross and Caligiuri130
demonstrated that continuous stimulation of CD56+ NK cells
with IL-15 + IL-12 in vitro results in NK cell apoptosis mediated
through an autocrine TNF--dependent mechanism, initiated after 24 hours of monokine stimulation. This may represent one means whereby the
innate immune system limits itself after prolonged activation.130
NK cells also produce the C-C chemokines macrophage inflammatory protein (MIP)-1 and MIP-1 after stimulation with IL-15, which is augmented with the addition of IL-12.131,136,137
Because C-C chemokines also serve as chemoattractants for NK
cells,138 IL-15 + IL-12-induced MIP-1 and
MIP-1 production may be one mechanism for proper trafficking of
additional NK cells to the site of infectious insult. In addition,
chemokine production may have implications in the interactions between
macrophages and NK cells, as MIP-1 has been shown to potentiate
IFN--inducible secretion of inflammatory cytokines by macrophages
such as IL-1.139 Further, NK cells costimulated with
IL-15 + IL-12 produce soluble factors (including C-C chemokines)
that inhibit human immunodeficiency virus (HIV)-1 replication in
vitro.137 The cytokine and chemokine profiles produced by
human NK cells in response to monokines IL-15 + IL-12 were
recently compared with those induced by monokines IL-18 + IL-12.132 Alone, IL-18, IL-15, or IL-12 induced little or
none of the cytokines examined, with the exception of IL-15-induced GM-CSF, MIP-1, and MIP-1. IL-18 + IL-12 induced extremely
high amounts of IFN- by CD56+ NK cells, with the
majority produced by the CD56bright NK cell subset.
IL-15 + IL-12 induced moderate amounts of IFN- but was also the
optimal stimulus for IL-10, TNF-, GM-CSF, MIP-1, and MIP-1.
This suggests that NK cell cytokine production may be governed in part
by the monokine milieu (including IL-15) induced during the early
pathogen-dependent response to infection, as well as the NK cell subset
present at the site of inflammation.132
As described earlier, there is now in vitro and in vivo evidence for
IL-15's participation in early innate immune cytokine responses,
especially those resulting in IFN- production by NK cells. Thus,
IL-15 acts as a costimulator of IFN- production by NK cells and may
therefore be important in the control of infections that require
IFN- for clearance.77 Additional in vivo studies of
IL-15's role during such infections may yield information to direct
therapies aimed at boosting the immune response to infection or
decreasing improper immune activation or inflammation. Because mice
genetically targeted to delete functional IL-15 or IL-15R gene
products concurrently lack NK cells,8,9 it will be
difficult to assess the role of IL-15 during the innate immune response in these models. Use of experimental systems that neutralize IL-15 will
be important to complement such IL-15/IL-15R knockout mice.
IL-15 and uterine NK cells.
In mice, the metrial gland is a uterine tissue that develops adjacent
to the placenta and contains granulated metrial gland cells that are
phenotypically and functionally uterine NK cells.140 Similar NK-like cells have also been identified in the human uterus and
have the phenotype
CD56brightCD16 IL-15 regulation of monocytes/macrophages and granulocytes Human macrophages express high-affinity binding sites for IL-15 that are up-regulated upon activation with LPS.28 Monocytes have been shown to express the IL-2/15R,149
c,150 and the IL-15R,30
suggesting the possibility for IL-15 to act in an autocrine fashion.
Human monocytes treated with IL-15 (10-1000 ng/mL) produced IL-8 and
macrophage chemotactic protein (MCP)-1 that was chemotactic
for neutrophils and monocytes, respectively.69 Alleva et
al151 demonstrated autocrine IL-15 regulation of macrophage proinflammatory cytokine production that was highly dependent upon the
concentrations of IL-15 available to the macrophage. Extremely low
(picomolar to attomolar) concentrations of IL-15 suppressed macrophage
proinflammatory (TNF-, IL-1, IL-6) cytokine production, but at high
concentrations it enhanced the production of these mediators.
Human neutrophils express the IL-2R IL-15 plays a role in the development, homeostasis, and
activation of TCR c, cell types that respond to ligation of
these receptors with IL-2 were logical potential targets for IL-15. In
addition to NK cells, several innate immune T-cell populations have
been shown to express the IL-2/15R or the c. These
include dendritic epidermal TCR T cells (DETCs), intestinal
intraepithelial lymphocytes (i-IELs), and NK1+ T cells
(NK-T cells).
DETCs are a skin-specific member of the TCR I-IELs consist of both TCR TCR Murine T cells that exhibit a restricted TCR repertoire (invariant
V Function of IL-15 on TCR , conferring responsiveness to IL-15. Such action on T cells
suggests that IL-15 expressed by APCs may be important for the early
activation of T cells at sites of inflammation immediately after TCR
ligation. Stimulation of TCR-engaged T cells with IL-15 has been shown
to induce various activation antigens, such as IL-2R (CD25),
IL-2/15R (CD122), FasL (CD95), CD30, TNFRII, CD40L, CD69, and
CD94/NKG2A,181-185 while down-regulating the
IL-15R.186 The in vitro proliferation of resting T
lymphocytes in response to anti-CD3 plus IL-15 was greatly reduced in
IL-15R/ lymphocytes compared with wild type,
supporting the idea that IL-15 requires induction of the IL-15R to
optimally stimulate resting T cells. Further,
IL-15R/ T cells showed a lower response to CD3
ligation plus IL-2, suggesting that IL-15R may be important for the
induction of IL-2R and hence responsiveness to IL-2.9
IL-15 also protected concanavalin A-activated human T lymphoblasts
from undergoing apoptosis after Fas or CD3 cross-linking or treatment
with dexamethasone in vitro and in vivo.187
IL-15 acts as a potent chemoattractant for T cells isolated from human
blood.188 This observation has led to a number of studies
examining the role of IL-15 during chronic inflammatory and autoimmune
diseases, such as rheumatoid arthritis (see below). IL-15R Jonuleit et al51 demonstrated that unstimulated human dendritic cell (DC) cultures produced low levels of IL-15 protein that were detectable by enzyme-linked immunosorbent assay and CTLL bioassay, and stimulated DC supernatants were shown to be chemoattractant for T cells. The production of IL-15 protein after phagocytosis51 or CD40 ligation191 provides an intriguing mechanism for initial attraction and stimulation of T cells in the absence of IL-2, as may be the case for other APCs such as macrophages.1,48,49,192 IL-15 stimulated the proliferation of human memory
(CD45RO+) CD4 and CD8 and naive (CD45RO) CD8+
human T cells in vitro, while having no effect on naive CD4 T lymphocytes, consistent with IL-2/15R Most reports support the classification of IL-15 as a proinflammatory
type-1 cytokine,193-198 whereas a few have observed IL-15 as a costimulator of type-2 cytokines.47,199,200 When
IL-15 has been used as an adjuvant to vaccination, a type-1 cytokine profile and increased IFN-
IL-15 expression has been detected in numerous tissues, many of
which are not sites of immune responses, indicating the potential for
additional nonimmune functions.1 Indeed, IL-15 also
affects cells outside of the immune system. IL-15 serves as an anabolic agent for skeletal muscle201 and may support muscle cell
differentiation.202 Intestinal epithelial cells signal and
proliferate in response to IL-15 in vitro.58 Vascular
endothelial cells express IL-15R
Role of IL-15 in autoimmune and inflammatory disease Rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic degenerative condition of
synovial membranes that is thought to be mediated in part by aberrant
cytokine regulation that ultimately results in abnormally high levels
of proinflammatory cytokines, such as TNF- , suggests some redundancy in the
factors responsible for T-cell extravasation into RA synovial membranes.205,207 Indeed, recent work has also documented
a role for IL-17208,209 and IL-18210 in the
pathophysiology of this disease, highlighting the complexity of the
cytokine cascades at work in RA. Subsequent studies also demonstrated
that IL-15-activated T cells from RA patients stimulated macrophage
cell lines and primary monocytes/macrophages to produce TNF- in
vitro.206 This effect was cell-contact dependent, and
antibodies to CD69, lymphocyte function-associated antigen (LFA)-1, and
intercellular adhesion molecule (ICAM)-1 inhibited the
T-cell-induced production of TNF- by macrophages. An increased
expression of IL-15 protein in the synovium of RA in comparison with
osteoarthritis patients has also been documented.211 In
the mouse, administration of soluble IL-15R prevents
collagen-induced arthritis, suggesting that development of effective
IL-15-blocking agents such as soluble receptors or MoAbs may be useful
in the treatment of RA.212
Sarcoidosis. Sarcoidosis is a chronic granulomatous condition of unclear etiology that progressively affects multiple organs, especially the lungs.213 Agostini et al214 suggested a potential role for IL-15 during the pathogenesis of pulmonary sarcoidosis because alveolar macrophages isolated from patients with active sarcoidosis expressed IL-15 mRNA and cytoplasmic or membrane IL-15 protein, whereas patients with inactive disease or normal donors did not. In addition, CD4+ T cells isolated from bronchoalveolar lavage of patients with active sarcoidosis expressed components of the IL-2/15R complexes and proliferated in response to IL-15, suggesting that macrophages may provide a proliferative signal to T cells in the lungs during this disease process.214 Inflammatory bowel disease. Two major types of inflammatory bowel disease (IBD) commonly occur, ulcerative colitis (UC) and Crohn disease (CD), and are thought to represent inappropriate chronic inflammatory processes.215 Kirman and Nielsen216 demonstrated that patients with UC or severe CD had an increased percentage of PBMCs that expressed IL-15 protein, which was decreased after successful symptomatic treatment. Serum IL-15 was detectable in several patients with UC with moderate to severe disease (5 of 8 cases; range, 0-490 pg/mL), but was not detectable in CD patients or normal donors. In vitro, LPS activation of UC or CD patients' PBMCs resulted in further increases in intracellular IL-15 protein levels.216 IL-15 protein was detected from supernatants of rectal mucosal biopsy specimens, and IL-15 mRNA was detected in macrophages and epithelial cells by in situ hybridization from patients with active CD or UC, but not from healthy controls. Further, lamina propria mononuclear cells from IBD patients proliferate in response to rIL-15.217 Recent studies have confirmed IL-15 protein production by macrophages in the mucosa of patients with IBD and provided evidence for T-cell modulation by IL-15 in this setting.218 These studies suggest that IL-15 released during chronic bowel inflammation may contribute to the pathogenesis of UC, and possibly CD. Other autoimmune or inflammatory diseases.
Increased production of IL-15 during several other chronic inflammatory
conditions has also been observed, including hepatitis C-induced liver
diseases and multiple sclerosis.219-221 Elevated levels of
serum IL-15 protein have been measured in hepatitis C virus-infected
patients with chronic hepatitis, liver cirrhosis, and hepatocellular
carcinoma as compared with asymptomatic carriers and healthy
controls.219 The highest levels of IL-15 were found in
patients with hepatocellular carcinoma, who had significantly higher
IL-15 levels compared with all other groups studied (n = 11;
mean ± SD, 77.4 ± 78 pg/mL; P < .05). Treatment
with IFN- may be a useful target in such
cases.223
IL-15 and transplant rejection The immunologic rejection of allografted solid organs by the recipient is a complicated process that includes acute, subacute, and chronic subtypes and is a major obstacle in transplant medicine.224 Cytokines are thought to contribute to allograft rejection by promoting the infiltration and activation of recipient immune cells within the transplanted organ. IL-15 mRNA expression was detected in all 45 biopsies from transplanted kidneys (IL-2 in only 3 of 45) and was significantly increased in rejecting compared with nonrejecting grafts.225 Although IL-15 mRNA expression was detected in the majority of posttransplant livers and was up-regulated compared with nontransplanted liver tissue, no significant correlation was found between IL-15 expression and rejection.226 The failure of an antibody (BT563) that selectively blocks the high-affinity IL-2R pathway to prevent acute
rejection of heart allografts suggests that other cytokines, such as
IL-15, may be responsible for the T-cell proliferation during this
process.227 Further studies demonstrated IL-15 mRNA and
protein expression within CD68+ macrophages infiltrating
transplanted myocardium, with or without anti-IL-2R
treatment.228 Although the percentage of
IL-15+ cells invading the grafts did not directly correlate
with rejection grade, these studies suggest that IL-15 may be involved
in T-cell activation during heart allograft rejection in the absence of IL-2. Li et al229 observed that mice with targeted
disruption of IL-2 and IL-4
(IL-2//IL-4/ double knockouts) rejected
islet allografts, with robust intragraft expression of both IL-15 and
IL-7. In this animal model, blockage of the c receptor
significantly prolonged survival, suggesting that signals mediated by
IL-15 or IL-7, in the absence of IL-2 and IL-4, participate in acute
graft rejection. Collectively, these studies demonstrate a potential
role for IL-15 as a therapeutic target during the rejection of
transplanted solid organs that requires further investigation.
IL-15 and cancer HTLV-1-mediated adult T-cell leukemia.
Infection with HTLV-1 can result in adult T-cell leukemia (ATL), a
malignancy in which the early phases are associated with autocrine
production of IL-2 and expression of IL-2R components. However, later
phases lack IL-2 production while IL-2R components remain on the
surface of these leukemic cells.230,231 As described earlier, IL-15 was codiscovered as the IL-T fusion protein involving the R region of HTLV-1 fused with the 5' UTR of the IL-15 gene, and the
ATL cell line HuT-102 produced abundant IL-T/IL-15 protein within cell culture supernatants.4 Later it was discovered that HTLV-1 Tax protein transactivates IL-15 gene transcription through
a NF- Other lymphoid malignancies.
Cutaneous T-cell lymphoma (CTCL) broadly delineates a group of related
lymphoproliferative disorders of the skin, including mycosis fungoides
(MF) and Sezary syndrome (SS).235 Both IL-2 and IL-7 have
been implicated as important growth factors for CTCL cells; however,
the etiology of these disorders is actively being
investigated.236,237 Indeed, treatment of these patients with an IL-2 fusion toxin, thereby targeting IL-2/15R (NK cell)
populations.244 Zambello et al245 showed that
both CD3+ and CD3 cells isolated from LDGL
patients expressed all 3 of the IL-15R components (IL-2/15R,
c, and IL-15R) and proliferated in response to IL-15
in vitro. Although no IL-15 protein was detected in the serum or
CD14+ cell culture supernatants of these cells,
membrane-bound IL-15 was demonstrated on the surface of
CD3+ and CD3 cells from LDGL patients, but
not normal controls, by flow cytometry. This is in contrast to the lack
of IL-15 mRNA expression by RT-PCR in sorted LGLs from patients,
leaving the significance of surface IL-15 detected by flow cytometry
unclear. However, the chronic nature of this leukemia and the clear
role of IL-15 in the development of CD3+ NK-T and
CD3 NK cells suggest that the possible deregulation of
IL-15 expression in these patients should be pursued. Indeed, mice
engineered with an IL-15 transgene that lacks the normal
posttranscriptional checkpoints regulating IL-15 protein translation
and secretion have recently been described.68 These mice
exhibit an early lymphocytosis composed of NK and
CD8+CD44hi T cells. Later, a significant
fraction of IL-15 transgenic mice develop a fatal lymphocytic leukemia
with a
CD3+TCR+CD44+DX5±CD8±
phenotype. The clinical course and disease manifestations appear similar to those in patients with LGL leukemia.244,246,247
Thus, continued overexpression of IL-15 may predispose to chronic
lymphocytosis and eventually to malignant transformation of lymphocytes.
IL-15 has also been shown to induce the proliferation of normal B
cells,248 malignant B cells obtained from B-cell chronic lymphocytic leukemia and hairy cell leukemia,249 and the
M-07e acute myelogenous leukemia (AML) cell
line.250 IL-15R components are expressed on multiple
myeloma cells, and IL-15 may play a role in the autocrine propagation
of this malignancy.251
Solid tumors. IL-15 is normally expressed at the mRNA level in several organs, including skeletal muscle, skin, lung, and kidney. Their malignant counterparts, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma,252 melanoma,253 small cell lung cancer,12 renal cell carcinoma, glioblastoma, neuroblastoma, and mesothelioma, also express the IL-15 transcript.254 Intracellular protein was observed in melanoma cell lines253 and renal cancer cells,254 and low secretion of IL-15 was observed in a subset of osteosarcoma and rhabdomyosarcoma lines (4-8 pg/mL).252 However, a definitive role for IL-15 in the pathogenesis of solid tumors has not been demonstrated. IL-15 and infectious disease Human immunodeficiency virus.
IL-15, through its ability to mimic the actions of IL-2, has 2 opposing
effects in the HIV-infected patient: a potentially beneficial
augmentation of immune function137,255-261 and a
potentially detrimental activation of HIV
replication.189,258,262,263 Because both of these effects
have been observed in several experimental systems, any proposed use of
IL-15 in vivo to boost immunity in this immunocompromised population
must include careful analysis of HIV replication. Initial studies by
Seder et al255 demonstrated that IL-15 enhanced the
proliferative response of PBMCs from HIV-infected patients when
stimulated with polyclonal mitogens, tetanus toxoid, or HIV-specific
antigens. Patki et al256 showed that whereas IL-2 enhanced
both spontaneous and antigen-induced lymphocyte proliferation in
HIV-infected patients, IL-15 enhanced antigen-induced lymphocyte
function only with significantly less HIV-1 replication. IL-15, alone
and in combination with IL-12, enhanced deficient in vitro NK cell
activity in HIV-1-infected patients,264 and IL-15 + IL-12-stimulated NK cells isolated from HIV-infected patients produced
C-C chemokines and inhibited HIV-1 infection in vitro.137 Thus, a large body of evidence now suggests that IL-15 significantly improves innate and antigen-specific immune cell function in
HIV-1-infected patients in vitro, in some cases better than IL-2.
While evidence documents that IL-15 may increase HIV-1 replication in
PBMCs and cell lines in vitro, it remains unclear whether the benefits
of IL-15 may be achieved at concentrations that do not affect viral loads in vivo. It is encouraging that IL-2 has been used successfully in vivo at low doses to boost immune function in HIV-infected patients,
without increases in HIV viral load.95,96,98 Thus, IL-15
is poised as a potential candidate for cytokine therapy in HIV-1
patients that may provide the benefits of IL-2 plus additional immune
modulation because of distinct IL-2/15R Other viral and bacterial pathogens.
IL-15 mRNA levels are elevated in PBMCs from patients with another
HTLV-1-mediated disease, HTLV-1 myelopathy/tropical spastic paraparesis (HAM/TSP), compared with normal donors.265
Antibodies against IL-15 or its receptor blocked spontaneous
proliferation of HAM/TSP PBMCs and, when combined with anti-IL-2
antibodies, completely abrogated proliferation. This suggests that dual
autocrine loops, including both IL-15/IL-15R and IL-2/IL-2R, may
promote lymphocyte proliferation in this disorder.265 In
vitro infection of human PBMCs with human herpesvirus (HHV)-6, HHV-7,
herpes simplex virus type-1, or Epstein-Barr virus resulted in
IL-15-dependent increases in NK cell cytotoxicity and IFN- production. In contrast,
mice transgenic for the SSP-IL-15 expressed intracellular IL-15
protein, had defective T-cell IFN- production, and were susceptible
to Salmonella infection. Thus, it appears that in vivo,
overexpression of the LSP-IL-15 leads to IL-15 secretion, enhanced
CD8+ memory-type cell development, and enhanced host
defense against Salmonella, whereas overexpression of
SSP-IL-15 remains intracellular and limits T-cell IFN-
responses.22 rIL-15 has been successful as a vaccine
adjuvant in animals through boosting the production of Toxoplasma
gondii-specific CD8+ T cells.193
Continued explorations of additional animal models of infection, as
well as delineation of the mechanism(s) of the action of IL-15 during
host defense, are needed to fully understand its role during both
innate and specific immune responses.
IL-15 and toxicity For IL-15 to be considered for use as an immunomodulator in humans, it must be determined whether such exogenous provision will result in toxicity for the patient. Whereas IL-15 administration (3 × 105 U/mouse/d) did not result in mortality when provided alone to mice over the course of at least 10 to 14 days, direct coadministration of IL-15 + IL-12 (1 µg/d) to mice resulted in a lethal cytokine-induced shock cascade, indistinguishable from the lethal effects of IL-2 + IL-12.269 Depletion of NK cells or macrophages before administration of IL-15 and IL-12 provided protection from lethality, suggesting that these innate immune effector cells were the primary effectors during this cytokine-induced shock. Selective elimination of various inflammatory mediators (TNF-, IFN-, MIP-1, IL-1, IL-1-converting enzyme, Fas,
perforin, inducible nitrous oxide synthase (iNOS), or STAT1)
using mice with targeted disruptions or neutralizing antibodies
revealed that none of these, even in combination, were responsible for
the lethal shock-like reaction. Therefore, it is possible
that novel proinflammatory mediators are produced in this cascade. Of
note, in this model, modest doses of IL-15 become toxic only when
combined with IL-12.
The generalized Shwartzman reaction is a lethal cytokine-induced shock
response elicited by sequential priming and challenge with bacteria or
bacterial components (eg, LPS).270,271 IL-12-induced IFN- Several chemotherapeutic agents (eg, 5-fluorouracil [5-FU], irinotecan [CT-711]) have documented clinical efficacy against colon cancer, but severe mucosal toxicity remains a significant clinical problem.275 In rat models of colon carcinoma, exogenous administration of IL-15 protected against diarrhea, stomatitis, weight loss, and death induced by 5-FU and irinotecan and increased maximal tolerated doses and overall complete response.276,277 In contrast, exogenous IL-2 potentiated toxicities with no beneficial antitumor effect when used in combination with either chemotherapeutic agent. Although the clinical benefit observed in these 2 animal model systems requires additional study for confirmation of the apparent toxicity-limiting activity, these preclinical models suggest that IL-15 may be useful as a chemoprotective agent in certain therapies. IL-15 and immunodeficiency Thec, shared by receptors for IL-2, IL-4, IL-7,
IL-9, and IL-15, has been implicated in the etiology of X-linked
SCID.26,27 Similarly, the lack of Jak3, a downstream
signaling component of c, results in mice101
and humans102 with SCID. The severe immunodeficiency
associated with a nonfunctional c or Jak3 is likely
associated with its common usage by multiple cytokines (IL-7, IL-15,
IL-2, IL-4) important for lymphocyte development and homeostasis.
Although such mutations provide a molecular basis for SCID, a
significant portion of SCID patients have normal c/Jak3 activity. Recently, Gilmour et al104 described a patient
with an NK cell-deficient (T , NK, B+)
form of SCID, which retained c/Jak3 yet lacked
expression of IL-2/15R. Flow cytometric analysis of the lymphocyte
population showed a severe deficit in NK cells, a decrease in T cells,
and normal numbers of B cells. However, this patient had defective cellular and humoral immune responses that manifested as recurrent viral and fungal infections during his first year of life. This report
demonstrates that lack of IL-2/IL-15 signaling through IL-2/15R can
lead to SCID, with the most prominent deficit in the NK cell lineage,
thereby highlighting the importance of the human IL-15/IL-15R pathway
in vivo.
Potential therapeutic uses of IL-15 Out of the multitude of basic studies on the biology of IL-15 and preclinical models of human disease, it is important to identify those lines of investigation that point toward potential clinical benefit. Two major directions of immediate interest are immune augmentation through exogenous provision of IL-15 and immune down-regulation through elimination of improperly expressed IL-15. Additional clinical applications of IL-15 are emerging from basic and preclinical studies on this cytokine (eg, vaccine adjuvant) but require further development.Cytokine therapy with IL-15.
Numerous cytokines produced through recombinant DNA technology have now
been used successfully to expand or activate immune cells or their
progenitors in patients, including erythropoietin, G-CSF,
macrophage-CSF, GM-CSF, thrombopoietin, IL-11, IFN- Blockade of improperly expressed IL-15.
Agents that selectively block the action of improperly regulated
cytokines have also been successfully used in the clinic, one prime
example being soluble TNF receptor for inflammatory conditions.280,281 Several studies in murine models have
identified agents that can block the action of murine IL-15 in vivo,
including a soluble IL-15R
A remarkable amount of progress has been made in our understanding
of IL-15 biology, its role in the normal host immune response, and its
potential for participation in the pathogenesis of disease since its
discovery in 1994. Because IL-15 has pleiotropic activity that
ultimately results in immunoregulatory cross-talk between natural and
specific immune cells, it may now be considered a cytokine that bridges
the innate and adaptive immune systems (Figure 5). Unraveling the biology of IL-15 has
revealed some interesting surprises, such as the complex multifaceted
regulation of its gene expression and a potential nuclear function. The
large body of in vitro and in vivo evidence documenting the importance
of IL-15 during NK cell ontogeny may point toward some of the first therapeutic applications for this cytokine to augment immune function in patients with cancer or immunodeficiency. In contrast, the discovery
of IL-15's role in the pathogenesis of RA and shock may yield equally
fruitful therapies aimed at blocking improper immune activation. For
IL-15-based therapies to be rapidly translated into the clinical
arena, additional preclinical animal studies and phase I/II clinical
trials must be performed to solidify the rationale for broader
application in human disease.
We thank Anand Ponnappan (The Ohio State University) for assistance in the preparation of the manuscript and Christopher VanDeusen (Stanford University) for his assistance in generating the theoretical model of IL-15 structure. We also thank Drs Christine Biron and Jacques Peschon, as well as Megan Cooper and Jeffrey VanDeusen, for their critical review of the manuscript. We apologize to those investigators not cited in this review as a result of space limitations.
Submitted March 29, 2000; accepted July 26, 2000.
Supported by National Institutes of Health grants CA68458, CA65670, and P30CA16058. T.A.F. is the recipient of Medical Scientist Program (MSP) and Bennett fellowships from The Ohio State University College of Medicine and Public Health.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Michael A. Caligiuri, The Ohio State University, 458A Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210; e-mail: caligiuri-1{at}medctr.osu.edu.
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Z. Wu, H.-H. Xue, J. Bernard, R. Zeng, D. Issakov, J. Bollenbacher-Reilley, I. M. Belyakov, S. Oh, J. A. Berzofsky, and W. J. Leonard The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15R{alpha} function but is not required for trans-presentation Blood, December 1, 2008; 112(12): 4411 - 4419. [Abstract] [Full Text] [PDF]
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A. Kroemer, X. Xiao, N. Degauque, K. Edtinger, H. Wei, G. Demirci, and X. C. Li The Innate NK Cells, Allograft Rejection, and a Key Role for IL-15 J. Immunol., June 15, 2008; 180(12): 7818 - 7826. [Abstract] [Full Text] [PDF]
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A. I. Kokaji, D. L. Hockley, and K. P. Kane IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells J. Immunol., April 1, 2008; 180(7): 4391 - 4401. [Abstract] [Full Text] [PDF]
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M. T. M. Vossen, M. Matmati, K. M. L. Hertoghs, P. A. Baars, M.-R. Gent, G. Leclercq, J. Hamann, T. W. Kuijpers, and R. A. W. van Lier CD27 Defines Phenotypically and Functionally Different Human NK Cell Subsets J. Immunol., March 15, 2008; 180(6): 3739 - 3745. [Abstract] [Full Text] [PDF]
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M. Fujita, X. Zhu, K. Sasaki, R. Ueda, K. L. Low, I. F. Pollack, and H. Okada Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma J. Immunol., February 15, 2008; 180(4): 2089 - 2098. [Abstract] [Full Text] [PDF]
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D. de Totero, R. Meazza, M. Capaia, M. Fabbi, B. Azzarone, E. Balleari, M. Gobbi, G. Cutrona, M. Ferrarini, and S. Ferrini The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways Blood, January 15, 2008; 111(2): 517 - 524. [Abstract] [Full Text] [PDF]
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Y. M. Mueller, D. H. Do, S. R. Altork, C. M. Artlett, E. J. Gracely, C. D. Katsetos, A. Legido, F. Villinger, J. D. Altman, C. R. Brown, et al. IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses J. Immunol., January 1, 2008; 180(1): 350 - 360. [Abstract] [Full Text] [PDF]
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N. L. Alves, E. M. M. van Leeuwen, E. B. M. Remmerswaal, N. Vrisekoop, K. Tesselaar, E. Roosnek, I. J. M. ten Berge, and R. A. W. van Lier A New Subset of Human Naive CD8+ T Cells Defined by Low Expression of IL-7R{alpha} J. Immunol., July 1, 2007; 179(1): 221 - 228. [Abstract] [Full Text] [PDF]
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C. M Smyth, S. L Ginn, C. T Deakin, G. J Logan, and I. E Alexander Limiting {gamma}c expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors Blood, July 1, 2007; 110(1): 91 - 98. [Abstract] [Full Text] [PDF]
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C. Hsu, S. A. Jones, C. J. Cohen, Z. Zheng, K. Kerstann, J. Zhou, P. F. Robbins, P. D. Peng, X. Shen, T. J. Gomes, et al. Cytokine-independent growth and clonal expansion of a primary human CD8+ T-cell clone following retroviral transduction with the IL-15 gene Blood, June 15, 2007; 109(12): 5168 - 5177. [Abstract] [Full Text] [PDF]
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L. Chiossone, C. Vitale, F. Cottalasso, S. Moretti, B. Azzarone, L. Moretta, and M. C. Mingari Molecular analysis of the methylprednisolone-mediated inhibition of NK-cell function: evidence for different susceptibility of IL-2- versus IL-15-activated NK cells Blood, May 1, 2007; 109(9): 3767 - 3775. [Abstract] [Full Text] [PDF]
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M. Rafei, J. H. Wu, B. Annabi, L. Lejeune, M. Francois, and J. Galipeau A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex Blood, March 1, 2007; 109(5): 2234 - 2242. [Abstract] [Full Text] [PDF]
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 S. Vujisic, S. Z. Lepej, I. Emedi, R. Bauman, A. Remenar, and M. K. Tiljak Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23 Hum. Reprod., October 1, 2006; 21(10): 2650 - 2655. [Abstract] [Full Text] [PDF]
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D. K. Taylor, P. T. Walsh, D. F. LaRosa, J. Zhang, M. A. Burchill, M. A. Farrar, and L. A. Turka Constitutive Activation of STAT5 Supersedes the Requirement for Cytokine and TCR Engagement of CD4+ T Cells in Steady-State Homeostasis J. Immunol., August 15, 2006; 177(4): 2216 - 2223. [Abstract] [Full Text] [PDF]
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C. L. Sutherland, B. Rabinovich, N. J. Chalupny, P. Brawand, R. Miller, and D. Cosman ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15 Blood, August 15, 2006; 108(4): 1313 - 1319. [Abstract] [Full Text] [PDF]
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D. Sauce, M. Larsen, S. J. Curnow, A. M. Leese, P. A. H. Moss, A. D. Hislop, M. Salmon, and A. B. Rickinson EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15 Blood, July 1, 2006; 108(1): 11 - 18. [Abstract] [Full Text] [PDF]
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W. A. Verri Jr., T. M. Cunha, C. A. Parada, X.-q. Wei, S. H. Ferreira, F. Y. Liew, and F. Q. Cunha IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-{gamma}, endothelin, and prostaglandin PNAS, June 20, 2006; 103(25): 9721 - 9725. [Abstract] [Full Text] [PDF]
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M. P. Rubinstein, M. Kovar, J. F. Purton, J.-H. Cho, O. Boyman, C. D. Surh, and J. Sprent Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha} PNAS, June 13, 2006; 103(24): 9166 - 9171. [Abstract] [Full Text] [PDF]
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B. Meresse, S. A. Curran, C. Ciszewski, G. Orbelyan, M. Setty, G. Bhagat, L. Lee, M. Tretiakova, C. Semrad, E. Kistner, et al. Reprogramming of CTLs into natural killer-like cells in celiac disease J. Exp. Med., May 15, 2006; 203(5): 1343 - 1355. [Abstract] [Full Text] [PDF]
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Q. Yu, C. Tang, S. Xun, T. Yajima, K. Takeda, and Y. Yoshikai MyD88-Dependent Signaling for IL-15 Production Plays an Important Role in Maintenance of CD8{alpha}{alpha} TCR{alpha}beta and TCR{gamma}{delta} Intestinal Intraepithelial Lymphocytes J. Immunol., May 15, 2006; 176(10): 6180 - 6185. [Abstract] [Full Text] [PDF]
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M. Guma, M. Budt, A. Saez, T. Brckalo, H. Hengel, A. Angulo, and M. Lopez-Botet Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts Blood, May 1, 2006; 107(9): 3624 - 3631. [Abstract] [Full Text] [PDF]
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D. de Totero, R. Meazza, S. Zupo, G. Cutrona, S. Matis, M. Colombo, E. Balleari, I. Pierri, M. Fabbi, M. Capaia, et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells Blood, May 1, 2006; 107(9): 3708 - 3715. [Abstract] [Full Text] [PDF]
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C. L. Combe, M. M. Moretto, J. D. Schwartzman, J. P. Gigley, D. J. Bzik, and I. A. Khan Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite PNAS, April 25, 2006; 103(17): 6635 - 6640. [Abstract] [Full Text] [PDF]
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D. J. Stauber, E. W. Debler, P. A. Horton, K. A. Smith, and I. A. Wilson Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor PNAS, February 21, 2006; 103(8): 2788 - 2793. [Abstract] [Full Text] [PDF]
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J. C. Morris, J. E. Janik, J. D. White, T. A. Fleisher, M. Brown, M. Tsudo, C. K. Goldman, B. Bryant, M. Petrus, L. Top, et al. Preclinical and phase I clinical trial of blockade of IL-15 using Mik{beta}1 monoclonal antibody in T cell large granular lymphocyte leukemia PNAS, January 10, 2006; 103(2): 401 - 406. [Abstract] [Full Text] [PDF]
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L. Baranda, H. de la Fuente, E. Layseca-Espinosa, D. Portales-Perez, P. Nino-Moreno, G. Valencia-Pacheco, C. Abud-Mendoza, J. Alcocer-Varela, and R. Gonzalez-Amaro IL-15 and IL-15R in leucocytes from patients with systemic lupus erythematosus Rheumatology, December 1, 2005; 44(12): 1507 - 1513. [Abstract] [Full Text] [PDF]
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J. Giron-Michel, M. Giuliani, M. Fogli, D. Brouty-Boye, S. Ferrini, F. Baychelier, P. Eid, C. Lebousse-Kerdiles, D. Durali, R. Biassoni, et al. Membrane-bound and soluble IL-15/IL-15R{alpha} complexes display differential signaling and functions on human hematopoietic progenitors Blood, October 1, 2005; 106(7): 2302 - 2310. [Abstract] [Full Text] [PDF]
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N. L. Alves, F. A. Arosa, and R. A. W. van Lier IL-21 Sustains CD28 Expression on IL-15-Activated Human Naive CD8+ T Cells J. Immunol., July 15, 2005; 175(2): 755 - 762. [Abstract] [Full Text] [PDF]
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S. A. Perez, L. G. Mahaira, F. J. Demirtzoglou, P. A. Sotiropoulou, P. Ioannidis, E. G. Iliopoulou, A. D. Gritzapis, N. N. Sotiriadou, C. N. Baxevanis, and M. Papamichail A potential role for hydrocortisone in the positive regulation of IL-15-activated NK-cell proliferation and survival Blood, July 1, 2005; 106(1): 158 - 166. [Abstract] [Full Text] [PDF]
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R. Trotta, R. Parihar, J. Yu, B. Becknell, J. Allard II, J. Wen, W. Ding, H. Mao, S. Tridandapani, W. E. Carson, et al. Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation Blood, April 15, 2005; 105(8): 3011 - 3018. [Abstract] [Full Text] [PDF]
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J. S. Miller, Y. Soignier, A. Panoskaltsis-Mortari, S. A. McNearney, G. H. Yun, S. K. Fautsch, D. McKenna, C. Le, T. E. Defor, L. J. Burns, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer Blood, April 15, 2005; 105(8): 3051 - 3057. [Abstract] [Full Text] [PDF]
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N. Gill, K. L. Rosenthal, and A. A. Ashkar NK and NKT Cell-Independent Contribution of Interleukin-15 to Innate Protection against Mucosal Viral Infection J. Virol., April 1, 2005; 79(7): 4470 - 4478. [Abstract] [Full Text] [PDF]
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Y. Li, W. Zhi, P. Wareski, and N.-p. Weng IL-15 Activates Telomerase and Minimizes Telomere Loss and May Preserve the Replicative Life Span of Memory CD8+ T Cells In Vitro J. Immunol., April 1, 2005; 174(7): 4019 - 4024. [Abstract] [Full Text] [PDF]
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A. Liu, J. L. Arbiser, A. Holmgren, G. Klein, and E. Klein PSK and Trx80 inhibit B-cell growth in EBV-infected cord blood mononuclear cells through T cells activated by the monocyte products IL-15 and IL-12 Blood, February 15, 2005; 105(4): 1606 - 1613. [Abstract] [Full Text] [PDF]
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O. Alpdogan, J. M. Eng, S. J. Muriglan, L. M. Willis, V. M. Hubbard, K. H. Tjoe, T. H. Terwey, A. Kochman, and M. R. M. van den Brink Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation Blood, January 15, 2005; 105(2): 865 - 873. [Abstract] [Full Text] [PDF]
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C. Munz, T. Dao, G. Ferlazzo, M. A. de Cos, K. Goodman, and J. W. Young Mature myeloid dendritic cell subsets have distinct roles for activation and viability of circulating human natural killer cells Blood, January 1, 2005; 105(1): 266 - 273. [Abstract] [Full Text] [PDF]
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M. Wysocka, B. M. Benoit, S. Newton, L. Azzoni, L. J. Montaner, and A. H. Rook Enhancement of the host immune responses in cutaneous T-cell lymphoma by CpG oligodeoxynucleotides and IL-15 Blood, December 15, 2004; 104(13): 4142 - 4149. [Abstract] [Full Text] [PDF]
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D. V. Baev, X.-h. Peng, L. Song, J. R. Barnhart, G. M. Crooks, K. I. Weinberg, and L. S. Metelitsa Distinct homeostatic requirements of CD4+ and CD4- subsets of V{alpha}24-invariant natural killer T cells in humans Blood, December 15, 2004; 104(13): 4150 - 4156. [Abstract] [Full Text] [PDF]
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C.-S. Park, S.-O. Yoon, R. J. Armitage, and Y. S. Choi Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form J. Immunol., December 1, 2004; 173(11): 6676 - 6683. [Abstract] [Full Text] [PDF]
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Z. Fehervari and S. Sakaguchi Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells Int. Immunol., December 1, 2004; 16(12): 1769 - 1780. [Abstract] [Full Text] [PDF]
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L. A. Lieberman, E. N. Villegas, and C. A. Hunter Interleukin-15-Deficient Mice Develop Protective Immunity to Toxoplasma gondii Infect. Immun., November 1, 2004; 72(11): 6729 - 6732. [Abstract] [Full Text] [PDF]
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S. Ferrari-Lacraz, E. Zanelli, M. Neuberg, E. Donskoy, Y. S. Kim, X. X. Zheng, W. W. Hancock, W. Maslinski, X. C. Li, T. B. Strom, et al. Targeting IL-15 Receptor-Bearing Cells with an Antagonist Mutant IL-15/Fc Protein Prevents Disease Development and Progression in Murine Collagen-Induced Arthritis J. Immunol., November 1, 2004; 173(9): 5818 - 5826. [Abstract] [Full Text] [PDF]
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M. Eriksson, S. K. Meadows, C. R. Wira, and C. L. Sentman Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-{beta} J. Leukoc. Biol., September 1, 2004; 76(3): 667 - 675. [Abstract] [Full Text] [PDF]
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J.-M. Lee, C.-Y. Chung, W.-W. Chiang, Y.-H. Liou, C.-F. Chen, and N.-S. Liao IL-15R{alpha} Is a Negative Regulator of TCR-Activated Proliferation in CD4+ T Cells J. Immunol., September 1, 2004; 173(5): 3155 - 3164. [Abstract] [Full Text] [PDF]
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E. Mortier, J. Bernard, A. Plet, and Y. Jacques Natural, Proteolytic Release of a Soluble Form of Human IL-15 Receptor {alpha}-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist J. Immunol., August 1, 2004; 173(3): 1681 - 1688. [Abstract] [Full Text] [PDF]
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G. Vamosi, A. Bodnar, G. Vereb, A. Jenei, C. K. Goldman, J. Langowski, K. Toth, L. Matyus, J. Szollosi, T. A. Waldmann, et al. IL-2 and IL-15 receptor {alpha}-subunits are coexpressed in a supramolecular receptor cluster in lipid rafts of T cells PNAS, July 27, 2004; 101(30): 11082 - 11087. [Abstract] [Full Text] [PDF]
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C. Ratthe and D. Girard Interleukin-15 enhances human neutrophil phagocytosis by a Syk-dependent mechanism: importance of the IL-15R{alpha} chain J. Leukoc. Biol., July 1, 2004; 76(1): 162 - 168. [Abstract] [Full Text] [PDF]
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M. L. Jison, P. J. Munson, J. J. Barb, A. F. Suffredini, S. Talwar, C. Logun, N. Raghavachari, J. H. Beigel, J. H. Shelhamer, R. L. Danner, et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease Blood, July 1, 2004; 104(1): 270 - 280. [Abstract] [Full Text] [PDF]
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J. Bernard, C. Harb, E. Mortier, A. Quemener, R. H. Meloen, C. Vermot-Desroches, J. Wijdeness, P. van Dijken, J. Grotzinger, J. W. Slootstra, et al. Identification of an Interleukin-15{alpha} Receptor-binding Site on Human Interleukin-15 J. Biol. Chem., June 4, 2004; 279(23): 24313 - 24322. [Abstract] [Full Text] [PDF]
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A. Bouchard, C. Ratthe, and D. Girard Interleukin-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors: role of Mcl-1 and decreased activity of caspase-3 and caspase-8 J. Leukoc. Biol., May 1, 2004; 75(5): 893 - 900. [Abstract] [Full Text] [PDF]
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M. M. W. Chong, Y. Chen, R. Darwiche, N. L. Dudek, W. Irawaty, P. Santamaria, J. Allison, T. W. H. Kay, and H. E. Thomas Suppressor of Cytokine Signaling-1 Overexpression Protects Pancreatic {beta} Cells from CD8+ T Cell-Mediated Autoimmune Destruction J. Immunol., May 1, 2004; 172(9): 5714 - 5721. [Abstract] [Full Text] [PDF]
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G. G. Neely, S. Epelman, L. L. Ma, P. Colarusso, C. J. Howlett, E. K. Amankwah, A. C. McIntyre, S. M. Robbins, and C. H. Mody Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling J. Immunol., April 1, 2004; 172(7): 4225 - 4234. [Abstract] [Full Text] [PDF]
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C. Petrovas, Y. M. Mueller, I. D. Dimitriou, P. M. Bojczuk, K. C. Mounzer, J. Witek, J. D. Altman, and P. D. Katsikis HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL J. Immunol., April 1, 2004; 172(7): 4444 - 4453. [Abstract] [Full Text] [PDF]
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J. Castelli, E. K. Thomas, M. Gilliet, Y.-J. Liu, and J. A. Levy Mature dendritic cells can enhance CD8+ cell noncytotoxic anti-HIV responses: the role of IL-15 Blood, April 1, 2004; 103(7): 2699 - 2704. [Abstract] [Full Text] [PDF]
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H. J. P. M. Koenen, E. Fasse, and I. Joosten IL-15 and Cognate Antigen Successfully Expand De Novo-Induced Human Antigen-Specific Regulatory CD4+ T Cells That Require Antigen-Specific Activation for Suppression J. Immunol., December 15, 2003; 171(12): 6431 - 6441. [Abstract] [Full Text] [PDF]
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W. N. D'Souza and L. Lefrancois IL-2 Is Not Required for the Initiation of CD8 T Cell Cycling but Sustains Expansion |
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Introduction
Molecular and cellular biology...
) and stop codons (
) are indicated;
in2 indicates intron 2.
2) were unable to bind IL-15, raising the possibility that
chain protein similar to mature
peripheral blood NK cells.
