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HEMATOPOIESIS
From the Departments of Immunology and Pediatrics,
University of Washington, Seattle; and the Basel Institute for
Immunology, Switzerland.
The zinc-finger protein Ikaros plays an important role in lymphoid
homeostasis, and loss of Ikaros expression through germline disruption
impairs lymphoid development. However, the role played by Ikaros after
commitment to the T-cell lineage is unclear. To address this question,
this study used the lck proximal promoter to drive the expression in
T-cell progenitors of a naturally occurring short Ikaros isoform (IK5),
which lacks the DNA-binding domain, reasoning that IK5 will form
heterodimers with long isoforms and perturb their function. The IK5
transgene led to a selective and dramatic decrease in extrathymic
intestinal intraepithelial lymphocytes (IELs) and natural
killer 1.1+ T (NK T) cells with little effect on
conventional Ikaros and its related family members, Aiolos and
Helios, are DNA-binding proteins that appear to regulate the
development and function of lymphoid cells at multiple stages (reviewed
in Cortes et al1). Ikaros is expressed throughout lymphoid
development, in some myeloid lineages, and even in the earliest
hematopoietic stem cells (HSCs).2-4 Alternative splicing
of Ikaros messenger RNA (mRNA) leads to formation of multiple different
isoforms, which differ in biologic activity. Long Ikaros isoforms bind
to a core DNA-binding motif, whereas short isoforms do
not.5 However, short Ikaros isoforms form heterodimers
with long isoforms and may thereby inhibit the ability of long isoforms
to engage DNA.5 The predominant isoforms expressed
throughout T-cell development are the long isoforms (IK1 and
IK2),4 whereas short isoforms appear to be relatively more
abundant in some myeloid lineages and short-term engrafting
HSCs.3
Ikaros is critically important for the normal development of all
lymphoid cells. Ikaros null mice (IK Germline disruption of Ikaros may preclude a clear assessment of its
role at later stages by altering the development potential of HSCs for
both myeloid and lymphoid development.6,7 Thus, to explore
the role of Ikaros in committed lymphoid progenitors independent of
effects in HSCs and to determine the importance of the predominance of
long isoforms in developing T cells, we generated mice in which the
short Ikaros isoform IK5 was expressed exclusively in T-cell
progenitors. IK5 lacks the ability to bind the Ikaros core DNA-binding
motif but still contains the C-terminal zinc fingers required to form
dimers. Although IK5 transgene expression was modest and less than the
aggregate expression of the endogenous Ikaros isoforms, the development
of NK T cells and extrathymically derived intraepithelial lymphocytes
(IELs) was markedly and selectively impaired. These results indicate
that even after commitment to the T-lymphocyte lineage, the
predominance of long relative to short Ikaros isoforms is essential for
normal T-cell development.
Mice strains and transgenic mouse construction
Northern blot analysis
Western blot analysis Cells were collected and lysed in TNT buffer (50 mM Tris-HCL, 150 mM NaCl,1% Triton X-100).14 Total protein was quantitated using a Coomassie protein assay (Pierce). Each lane received either 40 µg protein or the lysates from 100 000 cells for the cell equivalent Western blots. The samples were separated by a 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel. After transfer to nitrocellulose by using a semidry transfer apparatus (Ellard Instrumentation), Ikaros was detected by using 1:1000 anti-C-terminal Ikaros antisera (provided by S. Smale, University of California, Los Angeles) and goat antirabbit-horseradish peroxidase at 1:3000 (Zymed). The enhanced chemiluminence system (New England Nuclear) was used to visualize bands.IEL preparations The small intestine was removed and Peyer patches were excised. After removing fecal matter, the intestines were first cut longitudinally and then cut into 1-cm pieces. The pieces were digested by using 1 mM EDTA in Hanks balanced salt solution (HBSS) at 37°C with repeated vortexing to separate lymphocytes from the epithelial sheathes. Aliquots were removed over time as the epithelial sheathes settled to the bottom. The first 2 aliquots were replaced with EDTA/HBSS, and subsequent aliquots were replaced with 5% fetal bovine serum in HBSS. Removed aliquots were pooled and concentrated before running over a nylon wool (Sigma) column. A 40%/75% Percoll (Sigma) gradient was used to further enrich for IELs before analysis.Cell staining and processing Cells were stained using anti-CD3 , CD4, CD5, CD8 , CD24,
CD43, IL-2R , IL-2R , V 8-TCR, TCR , TCR![]() (Pharmingen),
B220, NK1.1, CD8 , CD25, and CD44 (CalTag, South San Francisco, CA).
Antibodies to IL-7R were obtained from Andy Farr (University of
Washington, Seattle). The antibodies were directly conjugated to
phycoerythrin (PE), fluorescein isothiocyanate (FITC), Tricolor (TC),
CyChromeC (CyC), PharRed, Allophycocyanin (APC), or biotin. Those
antibodies labeled with biotin were secondarily stained with
streptavidin (SA)-TC. Bead depletions were performed following the
manufacturer's instructions by using Dynal SA-magnetic beads and
biotinylated antibodies.
Generation of transgenic mice that express the Ikaros isoform IK5 Transgenic mice were generated in which IK5 was expressed under the control of the immunoglobulin heavy chain enhancer (Eµ and the lck proximal promoter (Figure 1A),8 which hereafter are referred to as bi-5 mice. The transgene mRNA was expressed in thymocytes, with reduced expression in splenocytes and total bone marrow (Figure 1B). After normalizing transgene expression to an elongation factor control, the 2 lines of bi-5 mice (lines 747 and 5516) appeared to express transgene mRNA in thymocytes in approximately similar amounts. By reverse transcriptase (RT)-PCR, expression of the transgene mRNA in NK cells and in mature T cells was approximately 5- to 10-fold less than in CD4+CD8+ double-positive (DP) thymocytes (data not shown). This is consistent with previous data, indicating that expression directed by this promoter/enhancer is highest in T-cell progenitors.8,15 Western blot analysis (Figure 1C) indicated that the abundance of IK5 protein in the thymus of bi-5 mice was similar to or somewhat less than the abundance of the full-length isoform IK1 and the slightly shorter isoform IK2. IK5 protein was expressed in CD4 CD8 (double- negative [DN]) and DP
thymocytes of the bi-5 mice but was not detected in splenic T cells of
bi-5 mice or in thymocytes or splenic T cells of controls (Figure 1D).
Ikaros protein was not detected in the livers of bi-5 or littermate
control mice (Figure 1C). IK5 mRNA was detected by sensitive
isoform-specific RT-PCR in thymocytes from control mice, indicating
that this isoform is expressed normally but in low abundance relative
to the long isoforms (data not shown).
NK T cells are reduced in the bi-5 mice On the basis of the pattern of expression, the IK5 transgene was predicted to target developing T cells. Yet, contrary to the observations in Ikaros / and IK-DNA /
mice, the bi-5 transgene had little effect on the development of
conventional CD4+ and CD8+ ![]() T cells,
thymic ![]() T cells, NK cells, or B cells. The proportions of these
cell populations in the spleen, thymus, and bone marrow were similar in
bi-5 transgenic mice and littermate controls (Figure 2). There was a slight reduction in
thymocyte numbers in bi-5 mice, which averaged 75% of normal
(Figure 2D).
A more striking difference was found in the percentage and numbers of
NK T cells. These cells have both NK and T-cell markers and are capable
of developing in thymectomized mice.16 Thymic NK T cells
are defined as HSAlo/
Extrathymically derived IELs are severely reduced Like NK T cells, IELs are derived extrathymically, at least in part.16,21 Normal mice have relatively similar numbers of![]() TCR+ IELs (![]() -IEL) and ![]() TCR+
IEL (![]() -IEL). The overwhelming majority of ![]() -IELs express the CD8![]() coreceptor as a homodimer, whereas ![]() -IELs may express
CD8![]() , CD8![]() , CD4, or no coreceptor.22 There is
considerable evidence to suggest that CD8![]() expression only occurs
on extrathymically derived IELs.23,24 The bi-5 mice had a
drastic reduction in the percentage and number of ![]() -IELs and a
corresponding increase in the percentage of ![]() -IELs (Figure
4A). Among the ![]() -IELs, there was a
decrease in the percentage of cells using CD8![]() and an increase in
the percentage of cells using CD8![]() cells in bi-5 mice compared with littermate controls (Figure 4B). Thus, bi-5 mice had reductions both in NK T cells and in extrathymically derived IELs.
Reduced expression of IL-2R and the common cytokine receptor
chain.25,26 For IL-15-specific binding, IL-15R is
also required.26 Like bi-5 mice, knockouts of IL-2R and
IL-15R or IRF-1 (a molecule required for IL-15 to be produced) have
severely reduced extrathymically derived IELs and NK T cells but very
mild defects in conventional ![]() T-cell
development.27,28 Because IL-2R expression is
restricted to hematopoietic cells, whereas IL-15R and IL-15 have
more ubiquitous expression patterns,25,29 we first
evaluated IL-2R expression on progenitors common to both ![]() and
NK T cells.17 IL-2R is expressed on DN thymocytes and
is down-regulated as cells mature to the DP stage.9 For this reason, thymocytes were gated on the DN population and analyzed for the expression of IL-2R on CD44+ (pro T1/pro T2) and
CD44 (pro T3/pro T4) cells.30 The expression
of IL-2R on CD44+ and CD44 DN thymocytes
from both lines of bi-5 mice was substantially reduced compared with
control mice (Figure 5A). Among
CD44 DN thymocytes, IL-2R expression was restricted to
the proT4 (CD44 CD25 ) subset and was
substantially reduced on cells from bi-5 mice compared with controls
(data not shown).
Because NK T cells are known to express IL-2R Partial restoration of T-cell development in bi-5 mice by a
bcl-xL transgene but not by an IL-2R expression on T-cell progenitors. Two approaches were used to address
this possibility.
IL-2R
The restoration of CD8
Comparison between bi-5 mice and mice with Ikaros gene disruptions Our studies demonstrate that enforced expression of IK5 in committed T-cell progenitors of bi-5 mice alters cell fate by selectively impairing the development or survival of NK T cells and extrathymically derived IELs. This phenotype was observed in 2 independent lines of bi-5 mice and differs greatly from those of IK / and the IK-DNA / mice. T-cell number
is markedly reduced and CD4+ T cells are enriched in adult
IK / mice,4 and T cells are absent in
IK-DNA / mice.3 The much more profound
defects in IK / and IK-DNA / mice
compared with bi-5 and IK-DNA+/ mice likely reflect
differences both in the magnitude and in the timing of the defect in
Ikaros expression. In IK-DNA / mice, long Ikaros isoform
expression is abolished and only short isoforms are expressed beginning
in HSCs and continuing thereafter in their cellular progeny, whereas in
bi-5 mice IK5 transgene expression commences in committed T-cell
progenitors and declines in mature T cells (Figure 1B,D), paralleling
the normal pattern of activity of the lck proximal
promoter.8
Mice that are heterozygous for the Ikaros DNA-binding domain disruption
(IK-DNA+/ Reduced IL-2R on DN T-cell progenitors. Like bi-5 mice, the numbers of NK T cells and ![]() -IELs are dramatically reduced in IL-2R and IL-15R knockout
mice,27,42 suggesting that reduced expression of IL-2R
might account for these effects of the bi-5 transgene. Similarly,
although the genes downstream of Ikaros that contribute to the striking
phenotypes observed in Ikaros knockout mice have not been clearly
defined, recent studies suggest that impaired expression of the flt-3
receptor and of c-kit ligand on HSCs and early T-cell progenitors may
contribute.1,7,41 Consistent with this notion, the
impaired development of lymphoid dendritic cells from human
CD34+ progenitors that overexpress IK7 was associated with
and may have resulted in part from reduced flt-3 receptor
expression.7,41 It is possible that the reduced expression
of IL-2R on T-cell progenitors in bi-5 mice, and of flt-3 receptor
and c-kit ligand on hematopoietic progenitors in the studies with
Ikaros knockout mice,1,7,41 may be due in part to
reductions in progenitor populations that express these receptors and
cytokines. However, our studies on IL-2R (Figure 5) and the effects
of retrovirally transduced IK7 on flt-3 receptor in vitro41
suggest that this is unlikely to be the sole explanation. Rather, these
findings collectively suggest that Ikaros may regulate the expression
of cytokine and cytokine receptor genes that play sequential and necessary roles in the proliferation, survival, and differentiation of
lymphoid progenitors.43 Consistent with this model, there are 2 potential Ikaros binding motifs (GGGAA) in close proximity within
the promoter region of human IL-2R , and deletions that eliminate
these sites greatly reduced reporter expression in CAT transcription
assays.44,45 There is also at least one GGGAA motif within
the promoter of murine IL-2R (S.N.T., unpublished observations,
May 2000).
Although enforced expression of IL-2R How might the IK5 transgene perturb expression of IL-2R / and IK-DNA+/ mice
lack N-terminal Zn++ fingers. On the basis of studies
performed in vitro,46 these short isoforms can form dimers
with and function as dominant-negative inhibitors of long isoforms that
contain all 4 N-terminal Zn++ fingers.
Although originally proposed to regulate transcription directly, most
recent studies suggest that Ikaros regulates transcription primarily by
recruitment to target genes of macromolecular complexes, including the
Mi-2/NURD (nucleosome remodeling and histone deacetylation), mSIN3A
(histone deacetylase), and SWI/SNF chromatin remodeling complexes.2,48,49 SWI/SNF complexes may help to open
chromatin and facilitate transcription, whereas the Mi-2/NURD and
mSIN3A compact chromatin and impede transcription.50 Thus,
in bi-5 mice, IK5 could function as a dominant-negative inhibitor by
partially sequestering the DNA-binding isoforms away from the promoters of genes required for proper T-cell development, thereby impeding the
ability of endogenous longer Ikaros isoforms to facilitate transcription through the recruitment of SWI/SNF chromatin-remodeling complexes to these loci. An alternative explanation is that Ikaros represses the transcription of genes in developing T cells, either by
recruitment of the Mi-2/NURD and mSIN3A complexes1,50 or by
direct competition with transcription factors needed for gene expression, as it does at the
We thank Stephen Smale for discussions and Ikaros antisera; Michael
Grusby for the CD1
Submitted August 28, 2001; accepted September 24, 2001.
Supported in part by grants HD18184 and AI37107 and by grant T32CA09537 (S.N.T.) from the National Institutes of 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: Christopher B. Wilson, Dept of Immunology, University of Washington, Campus Box 357650, 1959 NE Pacific St, Seattle, WA 98195; e-mail: cbwilson{at}u.washington.edu.
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