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REVIEW ARTICLE
From the Immunology Section, Pediatric Branch, National
Cancer Institute, National Institutes of Health, Bethesda, MD.
Interleukin-7 (IL-7) was initially isolated
more than 10 years ago.1-4 Nevertheless, the complete set
of physiologic roles for this cytokine, especially those involving
lymphocyte homeostasis, have only recently been elucidated. After the
initial descriptions of effects on B-cell precursors, recognition that
IL-7 also has marked activity on immature5-7 and
mature8 T cells soon followed. Information from
gene-deleted mice showed IL-7 is a nonredundant cytokine for murine T
and B lymphopoiesis.9,10 Mutations in the The gene for human IL-7 is located on chromosome
8q12-13,17 spans 6 exons, and has open-reading frame of
534 base pairs (177 amino acids), including a 25-amino acid signal
peptide18 (Figure 1).
Homology between the human and the murine IL-7 sequence is 81% in the
coding regions and approximately 60% to 70% in the 5' and 3'
noncoding regions. Although human IL-7 has activity in murine cells,
murine IL-7 fails to stimulate human pre-B cells. The sequence of human
IL-7 predicts a molecular weight of 17.4 kd, but glycosylation results
in an active protein of 25 kd. IL-7 is classified as a type 1 short-chain cytokine of the hematopoietin family, a group that also
includes IL-2, IL-3, IL-4, IL-5, granulocyte macrophage-colony-stimulating factor (GM-CSF), IL-9, IL-13, IL-15, M-CSF, and stem cell factor (SCF).
Production of IL-7 has been detected from multiple stromal
tissues, including epithelial cells in thymus and bone
marrow.19,20 Within the thymus, the predominant cell
responsible for IL-7 production appears to be a major
histocompatibility complex (MHC) class II+ epithelial cell that likely
represents a cortical epithelial cell.21 Additional sites
of IL-7 production include intestinal epithelium,22 keratinocytes,23 fetal liver,24 adult
liver,25 dendritic cells,26,27 and follicular
dendritic cells.28 Importantly, IL-7 mRNA has not been
detected in normal lymphocytes, though production by Epstein-Barr virus
(EBV)-transformed lymphocytes has been reported.29 Thus,
IL-7 is essentially a tissue-derived cytokine, with the primary sources
stromal and epithelial cells in various locations, whereas bone
marrow-derived dendritic cells appear to be relatively minor sources
of IL-7. IL-7 has been shown to bind extensively to the extracellular
matrix-associated glycosaminoglycan, heparan sulfate, and
fibronectin Transforming growth factor- IL-7 is a member of the family of cytokines that signal through
the common cytokine gamma chain (
IL-7R Like other members of the hematopoietin receptor family, IL-7R IL-7 signaling involves a number of nonreceptor tyrosine kinase
pathways that associate with the cytoplasmic tail of the receptor. These include the Janus kinase/signal transducer and activator of
transcription (Jak/STAT) pathway, phosphatidylinositol 3-kinase (PI3-kinase), and Src family tyrosine kinases. Details of IL-7 signaling have been comprehensively reviewed elsewhere.51
Of note, IL-7 shares intracellular signaling molecules with a number of
other cytokines, and the exact mechanisms responsible for signaling specificity remain unclear.
In humans, mutations in Based on the information available, the following model for
IL-7-mediated signaling can be put forth (Figure 2). First, IL-7 binds
to IL-7R
B-cell development can be divided into distinct phases in mice
that can be characterized by surface phenotype (Figure
3).58 IL-7 was first
identified based on its capacity to induce the growth of immature B
lymphocytes.1-3 The generation of
IL-7-deficient10 and IL-7R
Although there is no doubt that supraphysiologic levels of IL-7
potently expand B-cell progenitors in mice, leading to the expansion of
the entire B-cell compartment, several questions remain regarding the
exact physiologic role for IL-7 in regulating the proliferation,
survival, and differentiation of developing B cells in normal mice. In
particular, developing murine B cells show significant changes in the
capacity and threshold for IL-7-induced proliferation, depending on
the exact stage in B-cell development. Pre-pro-B cells display a high
threshold for IL-7-induced proliferation, followed by a diminished
threshold at the pro-B-cell stage with a return of a higher threshold
at the pre-B-cell stage.67 Furthermore, IL-7-induced
proliferation of pre-pro B cells (before immunoglobulin rearrangement)
requires stromal contact,58,68 whereas IL-7 induces the
proliferation of pro-B cells (D-J rearranged) in a contact-independent
manner.33,69 One potential explanation for the stromal
cell requirement in pre-pro-B cells was provided by the recent
description of a heterodimeric "hybrid cytokine" formed by IL-7 and
the It was recently shown that assembly of the B-cell antigen receptor
(BCR) complex regulates IL-7-induced proliferation because pro-B cells
from RAG2 Whether IL-7 acts directly to induce BCR rearrangement or facilitates
antigen receptor rearrangement indirectly by acting as a trophic factor
that enhances the survival of cells undergoing BCR gene rearrangement
has been a controversial area in B-cell development. Corcoran et
al72 found impaired immunoglobulin gene rearrangements in
IL-7R In a number of cell types, including developing B cells, IL-7 can act
as a trophic factor. Thus, in addition to the proliferative effect of
IL-7 on developing B cells, IL-7 can maintain developing B cells by
providing a survival signal. This effect appears to involve the
modulation of bcl-2 family members, a group of intracellular, membrane-associated proteins that includes both proapoptotic and antiapoptotic members.75 Although this mechanism has been
well established for T cells (as will be discussed later), the role of
this pathway in developing B cells remains less clear. Transgenic expression of the antiapoptotic molecule bcl-2 was unable to restore B
lymphopoiesis in IL-7 synergizes with stromal-derived factor 1 (SDF-1)79 and SCF80 in inducing the proliferation of developing B cells, and the combination of IL-7 and flt3 ligand induces dramatic expansions of B cells in vitro.81 Furthermore, IL-7 and flt3 ligand can support B-cell generation within the thymus.82 Thus, in the physiologic setting, it is likely that factors such as SDF-1, SCF, and flt3 ligand work in concert with IL-7 to regulate B-cell development. In summary, it appears as if the proliferative effect of IL-7 on pro- and pre-B cells is tightly regulated within the marrow environment by a complex interaction between antigen receptor assembly, responsiveness to IL-7, and action of other B-cell growth factors. Mature B cells are generally incapable of responding to IL-7. However,
recent work has demonstrated that a least a subset of peripheral B
cells can become transiently IL-7 responsive. B-cell receptor antigen
diversity is generated during development by immunoglobulin gene
rearrangements mediated by recombinase-activating (RAG) genes. However,
secondary rearrangements, termed receptor editing, can occur in
IgM+IgD As discussed earlier, humans with SCID caused by IL-7R
The development of T cells within the thymus proceeds through a
complex series of stages (Figure 4). The
first stage is represented by
CD3
The process of T-cell development occurs within a relatively poorly
understood microenvironment. Anatomically, TN precursors enter the
thymus in or migrate to the subcapsular zone, then, as they mature,
proceed centrally through the cortex to the medulla from which mature
SP T cells emigrate to the peripheral circulation. Figure
5 shows the anatomic locations within the
thymus in the context of T-cell developmental stages. The supporting
cells within the thymus include epithelial cells, dendritic cells,
fibroblasts, and a variety of other cell types. These cells provide a
network of growth factors and other molecules that are critical for
T-cell development. IL-7 can be identified within the thymus of 13-day murine embryos coincident with the first wave of thymocyte
expansion.19 The production of IL-7 has been identified in
a subset of MHC class II+ epithelial cells21 that also
express SCF, another important growth factor for early
thymocytes.92 Interestingly, SCF synergizes with IL-7 in
thymocyte proliferation, but it also acts at an earlier stage to
up-regulate CD25 followed by IL-7- and SCF-mediated
proliferation,93 suggestive of the massive proliferation
of CD44+CD25+ thymocytes that is known to occur
in vivo. Thus, the orderly development and selection of mature T cells
occurs within the complex thymic microenvironment containing a variety
of critical factors, including IL-7.
Soon after the identification of IL-7 as a growth factor for developing
B cells, it was recognized that IL-7 also could induce the survival and
proliferation of immature thymocytes in culture.94 As in
B-cell development, differences in T-cell phenotype between IL-7 Expression of IL-7 under an immunoglobulin The administration of IL-7 following T-cell depletion has been evaluated in murine models as a potential modulator of immune reconstitution. In a report by Abdul-Hai et al,100 IL-7 administered after syngeneic bone marrow transplantation (BMT) resulted in a 12-fold increase in thymic cellularity. In addition, RAG-1 expression and V-D-J recombination were increased in IL-7-treated animals. Bolotin et al101 showed that the administration of IL-7 after BMT resulted in a more rapid normalization in thymic cellularity and thymic subsets. Furthermore, increased numbers of thymus-derived mature T cells were seen following BMT with IL-7 treatment.102 Thus, exogenous IL-7 enhances thymopoiesis after radiation-induced lymphopenia. The effects of IL-7 on developing thymocytes are multiple. Initial
experiments using the fetal thymic organ culture system revealed that
IL-7 could enhance the viability of thymocytes independent of a
proliferative effect.103,104 von Freeden-Jeffry et
al105 showed that bcl-2 protein is markedly decreased in
CD44+CD25+ thymocytes from
IL-7 Thus, IL-7 maintains the survival of early thymocytes during the TN
stage of development through the modulation of bcl-2 family members. In
addition, in concert with other growth factors such as SCF, IL-7
contributes to the expansion of T-cell precursors. The end result is
that sufficient numbers of T-cell precursors undergo TCR rearrangement
before the massive cell loss that occurs during positive and negative
selection. A lack of IL-7R IL-7 is absolutely critical for the development of IL-7 also appears to be directly involved in the induction of TCR
rearrangement. It has been difficult to definitively show whether IL-7
directly contributes to the process of gene rearrangement or simply
maintains the survival of cells undergoing the rearrangement process
because these effects are occur simultaneously (reviewed in
113). Recently, it has been demonstrated that IL-7
regulates accessibility of the TCR Taken together, the information available suggests the following role
for IL-7 during T-cell development in the thymus. After the migration
of precursor cells to the thymic subcapsular zone, IL-7, in concert
with other factors such as SCF, drives the proliferation TN precursors.
The relative role of IL-7 in relation to other proliferative signals in
vivo remains unclear. With the loss of CD44, these cells begin to
undergo rearrangement of the TCR Two other reports are noteworthy regarding the role IL-7 plays in
T-cell development. In terms of IL-7 signaling in the thymus, it was
recently demonstrated that PIM1, a proto-oncogene that may be involved
in pre-T-cell differentiation, partially restores thymic cellularity
in IL-7
Despite continued thymic T-cell development well into adulthood,
there is a marked age-related decline in thymic
function.118 The mechanisms underlying thymic atrophy
remain unclear.119 IL-7 has been investigated in this
regard because of its importance in T-cell development. Knowledge of
the relative availability of IL-7 during the thymic aging process is
critical to our general understanding of human T-cell development. In
mice, the action of IL-7 in fetal and adult thymi may be distinct.
Crompton et al120 demonstrated that the arrest in thymic
maturation in IL-7R
Although IL-7 is best known for its effects on developing B-cell
and T-cell populations, IL-7 also potently modulates mature T-cell
function.124 First, IL-7 costimulates for T-cell
activation by enhancing proliferation and cytokine production,
especially in the setting of suboptimal TCR triggering. Although some
of this effect is IL-2 dependent through the up-regulation of IL-2R A third major effect of IL-7 on mature T cells is the inhibition
of programmed cell death. Thus, IL-7 acts as a trophic factor for
mature T cells, similar to the effects observed on developing B and T
lymphocytes The fourth major effect of IL-7 on mature T cells is the direct
enhancement of lytic activity of classical
CD8+CD3+ cytotoxic T lymphocytes (CTLs), NK
lytic effectors, NKT cells,136,137 and
CD4
IL-7 effects on the development and function of lymphoid populations are not limited to B cells and T cells. IL-7 also influences the development and function of dendritic cell populations and mobilizes myeloid populations.145 Indeed, IL-7 treatment of TN thymocytes induces the development of thymic dendritic cells (DCs)146 and thymic macrophages,147 and when IL-7 production is inhibited, the generation of thymic DCs is substantially reduced, suggesting that physiologic levels of IL-7 are important in the development of thymic DCs.148 Similarly, in mice, IL-7-containing cocktails are capable of generating thymic DCs from early thymic progenitors, and the use of IL-7 in such cultures precludes the requirement for GM-CSF.149 The combination of flt3-ligand and IL-7 are particularly potent at expanding early thymic progenitors and can dramatically enhance thymic B-cell numbers.82 Therefore, though it is well recognized that the potent effects of IL-7 on early thymocyte progenitors play a central role in primary T-cell development, emerging data also suggest that IL-7 may influence the development of thymic dendritic cells and potentially thymic B cells as well. IL-7 treatment of mice leads to mobilization of hematopoietic
progenitors from the marrow to the spleen, thus increasing splenic colony-forming units and diminishing megakaryocytic colony-forming units.65,150 Spleen and peripheral blood from such
IL-7-mobilized mice can rescue lethally irradiated hosts, providing
evidence that IL-7 is an effective hematopoietic mobilizing
agent.151 It is also known that monocytes have receptors
for IL-7 and, at high concentrations of IL-7 (10-100 µg/mL)
monocytes, are induced to produce IL-6, tumor necrosis factor- In addition to the capacity of IL-7 to induce dendritic cell development, some populations of normal dendritic cells also produce IL-7. This is particularly notable given that IL-7 is not produced by other normal cells of the hematolymphoid system but rather is produced primarily by stromal and epithelial cells. Langerhans cells do not produce IL-7,154 but both CD1a+ and CD14-derived dendritic cells, generated from cord blood, show mRNA for IL-7.26 In addition, analysis of low-density DCs isolated from human peripheral blood reveals that resting DCs do not produce IL-7 but that IL-7 is produced following overnight culture.27 Furthermore, when low DC numbers are used to stimulate antigen-specific responses in vitro, IL-7 neutralization inhibited the activation of responding T-cell populations, and IL-7 therapy has been noted to enhance dendritic cell function in vivo.132 Thus, IL-7 production by dendritic cells may contribute a co-stimulatory effect that may be of physiologic significance when other co-stimulatory molecules are limiting, such as might occur with low dendritic cell numbers. Despite evidence that marrow-derived DCs can produce IL-7, studies evaluating the role of IL-7 in the maintenance of T-cell homeostasis (detailed below) have shown that a marrow-derived source for IL-7 is not necessary for the induction of T-cell responses to low-affinity antigens following T-cell depletion, which is known to require IL-7.13 Thus, the predominant source for IL-7 appears to be non-marrow-derived populations, particularly stromal and epithelial cells. Importantly, follicular dendritic cells, which appear to be important sources for IL-7 within the lymphoid niche and which play a role in B-cell isotype switching, are not marrow derived but rather are of a distinct nonhematopoietic lineage.28,155
Based on the myriad effects of IL-7 on mature T cells and antigen-presenting cell populations noted above, it is not surprising that IL-7 may serve to modulate immune responses in infectious disease or tumor models. Indeed, several investigators have shown that IL-7 is critical for in vitro expansion and maintenance of human and murine antigen-specific T-cell lines,134,139,140,156-160 and IL-7 was consistently as effective or more effective than IL-2 for maintaining these cells ex vivo. Similar effects were also observed on human cells in a unique model wherein human colon xenografts were implanted into immunodeficient mice and human allogeneic T cells were adoptively transferred with IL-7.161 In athymic T-cell-depleted hosts, the systemic administration of IL-7 dramatically enhances the number of T cells recovered following adoptive transfer.102,132 When IL-7 is administered in the context of male skin graft placement on athymic T-cell-depleted female mice, only 1% of the T-cell repertoire must be transferred to induce graft rejection, whereas 10% of the repertoire is required for graft rejection in the absence of IL-7.132 Thus, if the number of antigen-specific T cells is limiting in vivo, the addition of supraphysiologic levels of IL-7 can substantially reduce the required T-cell dose for a given effect. These effects are observed in athymic mice and require the transfer of mature T cells, thus illustrating the potent effects of IL-7 as an immune modulator independent of its effects on developing lymphocytes. Systemic administration of IL-7 has also been used in the Renca renal cell carcinoma model in which a 75% reduction in pulmonary metastases was observed concomitantly with increases in the total body number of T cells, NK cells, B cells, and macrophages. Interestingly, this was not associated with an increase in LAK activity, suggesting that classical CTLs mediated these responses.66 The combination of IL-7-induced effects on mature T cells and the
down-regulation of TGF- To improve on these responses, costimulatory molecules have been co-transfected with IL-7 into tumor cells by Cayeaux et al.164,165 Here, the combination of B7/IL-7 transduction was shown to recruit activated CD8+CD28+CD25+ cells to the site of implanted tumors. In a murine lung cancer model, the co-administration of IL-7 gene-modified tumor and intratumoral dendritic cell injection induced superior tumor rejection compared with IL-7 gene modification alone.166 Thus, though IL-7 appears to enhance the reactivity of intratumoral lymphocytes when produced in the local tumor microenvironment, it cannot substitute for co-stimulatory molecule expression. In addition, some investigators have transduced IL-7 directly into dendritic cells with subsequent intra-tumor injection.167 Although reports discussed above have shown that some dendritic cell populations produce IL-7, this occurs generally at low levels, and antigen-presenting cell capacity can be enhanced by high-level production. Indeed, in a murine lung cancer model, the transduction of dendritic cells with B7- and IL-7-induced tumor regression, enhanced dendritic cell trafficking to the lymph nodes and spleen, and led to systemic protection to rechallenge.168 In summary, the myriad effects of IL-7 on mature T cells and the
down-regulation of TGF-
Physiologic changes in T-cell-depleted hosts Following T-cell depletion, physiologic changes in the immune milieu are invoked that exaggerate the peripheral mechanisms of T-cell homeostatic regulation as a means toward the restoration of T-cell numbers. Perhaps the most obvious evidence for altered immunobiology in T-cell depletion is the well-known observation that T-cell-depleted (TCD) hosts engraft and expand adoptively transferred T cells to a greater extent than do T-cell-replete hosts,169-171 a process that has been variably termed peripheral expansion and peripheral homeostatic expansion. This peripheral homeostatic expansion of mature T cells is primarily responsible for the restoration of T-cell homeostasis following T-cell depletion in athymic mice172 and in many patients with T-cell depletion.173-175Recent work has shown that antigen drives peripheral homeostatic expansion, both in TCD and in T-cell-replete hosts.176,177 When high affinity or cognate antigen is supplied, responses are greatly exaggerated in TCD hosts compared to those observed in T-cell-replete hosts. However, TCD hosts also expand T cells in response to low-affinity antigens or self-antigens.12,178 Although the degree of expansion induced by low-affinity peptide is less than that induced by high-affinity peptide, it appears that proliferation to low-affinity antigens plays an important role in maintaining TCR repertoire diversity in T-cell depletion. When IL-7 is unavailable following T-cell depletion, proliferation and survival of T cells in response to low-affinity antigens is absent.12,13 Thus, IL-7 is required for the proliferation of T cells with TCRs specific for low-affinity antigens, which occurs in TCD hosts (reviewed in 179). IL-7 administration increases the rate of T-cell immune reconstitution after bone marrow transplantation or cytotoxic chemotherapy in mice.64,150,180 Part of this effect reflects the capacity of IL-7 for increasing thymopoiesis,101,102 but IL-7 also potently enhances the thymic-independent peripheral expansion of mature T cells following T-cell depletion.132 This is because of the combined effect of IL-7 in enhancing antigen-driven expansion of high-affinity clones and low-affinity clones in TCD mice treated with IL-7.102 Indeed IL-7 was the only cytokine tested capable of increasing homeostatic peripheral expansion in TCD hosts, whereas IL-2, IL-3, IL-6, and IL-12 were not active in this regard. IL-7 is also capable of inducing naive T-cell cycling, thus preserving T-cell repertoire diversity in the absence of cognate antigen.181,182 Furthermore, IL-7 therapy enhanced immune competence in TCD hosts, rendering them able to reject minor histocompatibility antigen-mismatched skin grafts despite profound T-cell depletion.132 In summary, IL-7 potently modulates T-cell immune reconstitution
through the combined effects of increasing thymic output and
enhancing homeostatic peripheral T cell expansion (Figure 7). Furthermore, IL-7 is absolutely
required for the recruitment of low-affinity ligands for peripheral
homeostatic expansion, and supraphysiologic IL-7 levels enhance the
magnitude of T-cell expansion to high-affinity, or cognate, antigens
and to low-affinity, or self, peptides.
IL-7 elevations in patients with T-cell depletion Studies of circulating IL-7 in TCD populations were initially performed by Bolotin et al,14 who found substantial elevations in circulating IL-7 in children after allogeneic BMT. Follow-up studies in multiple clinical cohorts with T-cell depletion have shown profound inverse relationships between circulating IL-7, as measured by a high-sensitivity enzyme-linked immunosorbent assay, and peripheral CD4 T-cell numbers in children and adults with T-cell depletion.15,16 In human immunodeficiency virus infection, elevated IL-7 levels decline as CD4 recovery occurs following effective antiviral therapy. In one cohort of patients with moderate total CD4 depletion but with more substantial depletion of the naive subset of CD4 cells, strong inverse correlations between circulating IL-7 and CD62L+CD45RA+CD4+ cells were observed that gradually disappeared with the recovery of the naive subset.15 Thus, isolated depletion of either total CD4+ T cells or the CD4+ naive subset appears capable of driving elevations in IL-7 levels. The strongest correlation exists between circulating IL-7 levels and CD4 counts, with weaker correlations between IL-7 and CD8+ T cells and B cells. It remains unknown whether isolated CD8 depletion might also be sufficient to raise circulating IL-7 levels. Similar relationships were not observed between circulating lymphocyte counts and IL-2, IL-4, IL-6, IL-12, or IL-15, suggesting that the relationship with IL-7 was unique.15Inverse relationships were also observed in children and young adults treated with cytotoxic chemotherapy for cancer in whom circulating IL-7 increases following chemotherapy induced CD4 depletion and IL-7 levels returned to baseline following CD4+ recovery after the completion of therapy.15 In patients with idiopathic CD4 lymphopenia, which comprises a heterogeneous group of patients with CD4 depletion of uncertain etiology,183 less significant relationships between CD4 counts and circulating IL-7 levels were observed. Here it was observed that, compared with other patients studied, a subset of patients had inappropriately low levels of circulating IL-7 for the degree of CD4 depletion present, suggesting that low IL-7 levels contribute to the development of CD4 lymphopenia.15 Recently, in HIV infection, subsets of patients with unexpectedly low levels of circulating IL-7 for the degree of CD4 depletion have also been identified as having diminished capacity to restore peripheral CD4+ T-cell numbers following effective antiviral therapy.184 Further studies are necessary to confirm whether low IL-7 levels in the face of CD4 depletion correlate with diminished capacity for immune reconstitution and to identify the reason for low IL-7 levels in some patients with CD4 depletion. Much work remains to be done to determine the mechanisms responsible for increasing circulating IL-7 levels in TCD hosts. It is not unknown whether IL-7 levels increase because of diminished adsorption by the reduced number of cells expressing IL-7R as a result of TCD, whether this reflects an increase in the production of IL-7, or both. Regardless of the mechanism, the physiologic effects of chronic IL-7 elevation in T-cell depletion are likely to be substantial. In summary, recent studies have shown that IL-7, through its potent effects on mature T cells, plays a central role in modulating peripheral T-cell expansion in states of T-cell depletion. In the emerging model, T-cell depletion results in increased levels of stromally produced IL-7, which leads to increased T-cell proliferation in response high-affinity and low-affinity antigens. As a result, TCD hosts show increased peripheral homeostatic expansion that not only enhances immune competence to antigens encountered during this time period but potentially maintains a relatively diverse repertoire by limiting the contraction that would occur if responsiveness was limited to only high-affinity antigens. This potential capacity of IL-7 to break tolerance to low-affinity antigens might predispose to autoimmunity or lymphoproliferation in some patients, but it might also prove to be exploitable in the context of vaccine trials for cancer and other diseases.
Because of space limitations, we have tried to focus predominantly on more recent developments. Thus, we thank the many investigators who performed important work but who were not referenced. We thank Scott Durum for his careful review of the manuscript and his helpful suggestions. The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States government.
Submitted August 1, 2001; accepted January 18, 2002.
Reprints: Terry J. Fry, Immunology Section, Pediatric Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 13N240, MSC 1928, 10 Center Dr, Bethesda, MD, 20892-1928; e-mail: tf60y{at}nih.gov.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.
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M. Otto, R. C. Barfield, W. J. Martin, R. Iyengar, W. Leung, T. Leimig, S. Chaleff, S. D. Gillies, and R. Handgretinger Combination Immunotherapy with Clinical-Scale Enriched Human {gamma}{delta} T cells, hu14.18 Antibody, and the Immunocytokine Fc-IL7 in Disseminated Neuroblastoma Clin. Cancer Res., December 1, 2005; 11(23): 8486 - 8491. [Abstract] [Full Text] [PDF]
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T. J. Fry, M. Moniuszko, S. Creekmore, S. J. Donohue, D. C. Douek, S. Giardina, T. T. Hecht, B. J. Hill, K. Komschlies, J. Tomaszewski, et al. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates Blood, March 15, 2003; 101(6): 2294 - 2299. [Abstract] [Full Text] [PDF]
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Top
Introduction
Genetics and structure
chain of the
IL-7 receptor in patients with severe combined immunodeficiency (SCID)
confirmed that IL-7 is indispensable for T-cell development in humans.
However, the presence of B cells in these individuals suggests
important differences between the role of IL-7 in murine and human
lymphocyte development.
4 variant, which lacks exon 4, has been found in multiple
tissues and lacks biologic activity. Whether this variant has any
biologic significance is unknown. The murine IL-7 gene has
approximately 80% homology to the human gene in the coding regions but
lacks the 54-base pair (bp) exon 5.
a feature that is likely to play an important role in the
regulation of local tissue availability and IL-7-induced signaling
within the microenvironment.
(TGF-
c) (Figure
/
light chain promoter
resulted in increases in all mature T-cell subsets but no increase in
pro-T cells.
)B(+)NK(+) severe combined immunodeficiency.
Nat Genet.
1998;20:394-397