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Doubly Deficient Mice Recapitulate the Thymic and Intraepithelial Lymphocyte (IEL) Developmental Defects of 
c-/- Mice: Roles for Both IL-2 and IL-15 in CD8 IEL Development1
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain-deficient (IL-7R-/-) and common 
chain-deficient (c-/-) mice both exhibit abnormal
thymic and intestinal intraepithelial lymphocyte (IEL) development, but
the developmental inhibition is not equivalent. In this report, we
assessed whether the defects in T cell development associated with
c-/- mice were due to currently defined c-dependent
cytokines by cross-breeding IL-7R-/- mice to mice
lacking either IL-2, IL-4, or IL-2Rß. IL-2/IL-7R and IL-4/IL-7R
double knockout (DKO) mice demonstrated equivalent thymic development
to IL-7R-/- mice, whereas IL-2Rß/IL-7R DKO mice,
which lack IL-2, IL-7, and IL-15 signaling, displayed thymic T cell
defects identical to c-/- mice. Collectively, these
data indicate that of the c-dependent cytokines, only IL-7 and IL-15
contribute to the progression and production of thymic T cells. In the
IEL, IL-7R-/- mice selectively lack CD8
TCR
cells, whereas IL-2Rß-/- mice show a
significant reduction in all CD8 cells. IL-2-/- and
IL-2/IL-7R DKO mice demonstrated a reduction in CD8 IELs to
nearly the same extent as IL-2Rß-/- mice, indicating
that IL-2 functions in CD8 IEL development. Moreover,
IL-2Rß/IL-7R DKO mice lacked nearly all TCR-bearing IEL, again
recapitulating the phenotype of c-/- mice. Thus, these
data point to the importance of IL-2, IL-7, and IL-15 as the
c-dependent cytokines essential for IEL
development. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain
(c)3 is a shared
subunit of the receptor complexes for IL-2, -4, -7, -9, and -15 which
consist of c, a cytokine-specific -chain, and for IL-2 and IL-15,
the shared IL-2Rß-chain (1).
c-/- mice lack signaling via all five of
these cytokines and exhibit severe hypocellularity of both B and T
cells and a virtual absence of intraepithelial lymphocytes (IEL) in the
intestine, reproductive tract, and other mucosa (2, 3).
This phenotype closely mirrors human X-linked severe combined
immunodeficiency, which results from mutations in the c gene
(4). By comparison, mice lacking either IL-7, IL-7R, or
treated with IL-7-specific mAb display similarly reduced B and T cell
numbers (5, 6, 7), whereas mice deficient in IL-2, IL-2R,
IL-2Rß, IL-4, IL-15R, doubly deficient in IL-2 and IL-4, or
treated with IL-9-specific mAb have no outward defects in the
production of thymus-dependent T cells (8, 9, 10, 11, 12, 13, 14).
Thymic cellularity is dramatically reduced 10- to 25-fold in both
IL-7R-/- mice and
c-/- mice, whereas the CD4/CD8 thymic subset
distribution observed in both of these mice remains essentially the
same as in wild-type mice (6). Although many aspects of
the thymic developmental defects associated with c-deficient mice
are accounted for by abrogated IL-7/IL-7R signaling, impaired IL-7R
function does not fully explain the thymic phenotype observed in
c-/- mice.
IL-7R-/- mice demonstrate an accumulation of
triple negative (TN) cells at both the
CD44+CD25- stage 1 and the
CD44+CD25+ to
CD44-CD25+ (stages 2–3)
transition, whereas c-/- TN cells are
blocked predominantly at the stage 2–3 transition only. Moreover,
c-specific mAb inhibited T cell development in irradiation chimeras
reconstituted with IL-7R-/- bone marrow
precursor cells, implicating one or more c-dependent cytokines other
than IL-7 in conventional thymic T cell development (14, 15).
Regarding extrathymic T cell development, the differences among
c-/- mice, anti-c mAb-treated
irradiation chimeras, and IL-7R-/- mice are
even more striking and clearly point to a developmental role for at
least one other c-dependent cytokine besides IL-7 (15).
The IEL of c-/- mice are essentially void of
all T lymphocytes, whereas IL-7-/- mice and
IL-7R-/- mice lack only the TCR subset
(2, 3, 16, 17). Typically, these thymus-independent
TCR cells comprise roughly half the IEL and express CD8 as a
homodimer, rather than the CD8ß coreceptor of thymic-derived CD8 T
cells. In normal mice, half of all TCRß IEL also express CD8
and are considered thymus-independent, whereas the remaining IEL
express a thymic-derived "conventional" phenotype consisting of
TCRß CD8ß and TCRß CD4 subsets (18).
IL-2Rß-/- and
IL-15R-/- mice also display significantly
reduced CD8 IEL of both TCR types (12, 19). Thus,
IL-15 appears to play a role in CD8 IEL development.
In this study we have assessed the potential contribution of
c-dependent cytokines besides IL-7 to conventional thymic and IEL T
cell development by cross-breeding either
IL-2-/-, IL-2Rß-/-,
or IL-4-/- mice to
IL-7R-/- mice to obtain multiple double
knockout (DKO) strains. Phenotypic analyses of these mice are
consistent with an important role for IL-15 in thymic and IEL
development. In addition, we have confirmed a role for IL-2, in
addition to IL-15, in CD8 IEL development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All single gene knockout mice were on the C57BL/6 genetic
background and were obtained from The Jackson Laboratories (Bar Harbor,
ME), except for c-/- mice (kindly provided
by W. Leonard, National Institutes of Health, Bethesda, MD, and D.
Wiest, Fox Chase Cancer Center, Philadelphia, PA) and
IL-2Rß-/- mice (kindly provided by T. Mak,
University of Toronto, Ontario, Canada). All mice were maintained under
virus-specific Ab free conditions. IL-2/IL-7R, IL-2Rß/IL-7R,
and IL-4/IL-7R DKO mice were generated through the interbreeding of
single gene deficient mice for three to five generations to obtain
doubly deficient lines. All mice were genotyped by PCR of genomic tail
DNA using gene-specific sets of differential primers: one common primer
to a nondeleted gene sequence present in both the mutant and wild-type
alleles, and an additional primer specific for either an inserted
neo sequence found in the mutant allele or a wild-type
sequence replaced by recombination in the knockout mouse. PCRs to
detect mutant and wild-type alleles were run separately to prevent
primer competition. Periodic Southern blot analysis of genomic tail or
liver DNA was conducted to confirm PCR genotyping using cDNA (IL-7R,
IL-2Rß) or genomic (IL-2, IL-4) probes.
Isolation of IEL
IEL were isolated using a modified procedure described by Poussier and Julius (20). Briefly, small intestine was trimmed of fat and Peyer’s Patches by manual dissection. Fecal contents were flushed with PBS, and longitudinally sectioned 0.5-mm segments were shaken vigorously in 50 ml of RPMI 1640 medium with 100 U/ml penicillin, 100 µg/ml streptomycin, 0.05 mM 2-ME, and 2.5% FCS at 37°C for 30 min to dislodge IELs from the epithelial lining. Supernatants were decanted through gauze and incubated without shaking at 37°C for at least 30 min to kill contaminating epithelial cells. Cell pellets were resuspended in 1.055 g/ml Percoll and layered over 1.085 g/ml Percoll. IEL were collected at the gradient’s interface after spinning 15 min at 1700 rpm and washed three times in HBSS before staining with fluorescent Abs.
Flow cytometric analysis
Biotinylated-NK1.1 (PK136), FITC-CD4 (GK1.5), FITC-CD25 (3C7),
and FITC-CD3 (145-2C11) were prepared in our laboratory.
Cychrome-CD8 (53-6.7), cychrome-CD4, cychrome-CD3, FITC-CD8ß
(53-5.8), biotinylated-CD44 (IM7), biotinylated-TCRß (H57-597),
biotinylated-TCR (GL3), and PE-streptavidin were purchased from
PharMingen (San Diego, CA). Purified mAbs specific for IL-2Rß (5H4)
and IL-7R (A7R34; kindly provided by S. Nishikawa, Kyoto University,
Kyoto, Japan) were described previously (21, 22).
Mouse-adsorbed biotinylated-anti-rat IgG (PharMingen) revealed with
PE-streptavidin was used in three-step staining to detect IL-2Rß and
IL-7R. All staining was performed for 20 min at 4°C in excess
concentrations of Ab. Forward and side scatter axes and propidium
iodide exclusion were used to set live lymphocyte gates from whole cell
preparations. In some IL-7R-deficient mice, we observed an increased
fraction of small cells with variable side scatter that partially
overlapped the live gate of smaller thymocytes yet did not express CD3,
CD4, CD8, c-kit, Thy-1.2, CD5, CD44, or CD25. Because
pro/pre-T cells are typically larger than the majority of thymocytes
(23), these cells were excluded from the analysis of TN
subsets. Between 5 and 10 x 103 gated
events were collected per sample on a Becton Dickinson FACScan, and
results were quantified using CellQuest software (Becton Dickinson, San
Jose, CA). Wild-type C57BL/6 or heterozygous littermates were analyzed
for comparison.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The thymic cellularity of adult IL-2/IL-7R DKO, IL-4/IL-7R
DKO, and IL-7R-/- mice were all similar
(5–10 x 106 cells/mouse; n
= 10 mice/group, aged 4–9 wk), with a 10- to 20-fold reduction in
thymic cell number. On the other hand, similarly aged IL-2Rß/IL-7R
DKO mice (n = 6) and c-/-
mice (n = 3) generally displayed smaller thymi than
IL-7R-/- mice (<5 x
106 cells/mouse). Moreover, older
IL-2Rß/IL-7R DKO mice (n = 2, aged >13 wk) had
extremely involuted thymi, which made cell recovery nearly impossible.
We have observed this same degree of thymic involution in similarly
aged c-/- mice, whereas complete thymic
involution is not observed in IL-7R-/- mice
until 1–2 mo later (data not shown). These data suggest a role for
IL-2Rß, most likely as a component of the IL-15R, along with IL-7R,
but not IL-2 and IL-4, in the production of thymic T cells.
TN thymic subsets in DKO mice
TN thymocytes are divided into four subsets of increasing maturity
(23) based on CD44 and CD25 expression. Stage 1 TN cells
(CD44+CD25-) consist of
the earliest defined thymic precursors, with multilymphoid lineage
potential, and thymic NK cells. TCRß, TCR, and TCR
rearrangements commence at TN stage 2
(CD44+CD25+), and both
pre-TCR and TCRß are expressed on the cell surface at TN stage 3
(CD44-CD25+). TN stage 4
(CD44-CD25-) is the last
point before up-regulation of CD4, CD8, and TCR rearrangements.
Despite the diminished number of thymocytes, the pattern of CD4/CD8
thymic subsets was usually comparable in all the DKO mice tested,
including the percentage of TN cells. The pattern of TN subsets,
however, in IL-7R-/- mice and
c-/- mice typically differed from each other
and from normal mice (Fig. 1
, Ref.
14). The TN subset distribution of IL-2/IL-7R DKO and
IL-4/IL-7R DKO mice was largely comparable to that seen in
IL-7R-/- mice (Fig. 1), although CD25
expression was somewhat more diffuse in the DKO mice. All these
patterns are characterized by an increased proportion of cells in stage
1 and the stage 2–3 transition. Thus, these data further indicate that
IL-2 and IL-4 play no obvious role in thymic T cell development. On the
other hand, IL-2Rß/IL-7R DKO mice exhibited a pattern of TN
subsets similar to c-/- mice, with a
characteristic block at the stage 2–3 transition and a decrease in
stage 1 cells. A similar decrease in stage 1 pro-T cells was also
observed in young IL-2Rß-/- mice of normal
thymic cellularity (Fig. 1). Thus, IL-2Rß/IL-7R DKO mice
recapitulate the thymic developmental defects of
c-/- mice.
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-/- mice.
NK1.1 expression was detected on 
50% of stage 1 cells in wild-type
mice, whereas this fraction increased to 75% in
IL-7R-/- mice. In contrast, the expression
of c-kit, a marker of T lineage precursors, was comparable
within individual TN cell subsets from
IL-7R-/- mice and normal mice (data not
shown), with a higher fraction of c-kit+
cells at stages 2 and 3 (50% of total cells) than at stage 1 or 4
(10% each). Thus, a portion of the increase in stage 1 TN cells is
due to a higher fraction of thymic NK cells. The expression of both
NK1.1 and c-kit in TN cells of IL-2/IL-7R DKO and
IL-4/IL-7R DKO mice were similar to that of
IL-7R-/- mice (data not shown).
Unexpectedly, weak NK1.1 staining was detected throughout stages 2 and
3 and, to a lesser extent, on stage 4 cells of
IL-7R-/- mice (Fig. 2A), but was undetectable on
CD4+CD8+ thymocytes. In
general, the level of staining at stages 2 and 3 was to 2- to 4-fold
higher than control staining in normal mice which exhibited no specific
staining for NK1.1 after TN stage 1 (Fig. 2B). This staining
of IL-7R-/- TN cells was further judged to
be specific by the capacity of unlabeled anti-NK1.1 to inhibit
staining by biotinylated-NK1.1/PE-streptavidin (data not shown). This
result raises the possibility that normal down-regulation of NK1.1 on
developing T cells requires IL-7R signaling. One
IL-7R-/- mouse, however, with a particularly
large thymus (31.2 x 106 cells)
demonstrated no NK1.1 staining beyond TN stage 1 (Fig. 2B).
This finding suggests that when there is reasonable compensation for a
loss of IL-7R function in vivo, NK1.1 expression on pro-T cells
undergoes normal regulation.
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on TN subsets
To assess the potential points in TN cell progression
dependent upon IL-7 and IL-2Rß, IL-7R and IL-2Rß expression was
measured in pro-T cell subsets of normal C57BL/6 mice. Both these
receptor subunits were expressed at high levels on stage 1 TN cells,
whereas only IL-7R was detected at all TN stages in young mice (Fig. 3). In older mice (>15 wk), expression
of IL-7R in stages 3 and 4 pre-T cells was usually lower, but still
detectable (data not shown). Thus, this pattern of expression is
consistent with IL-2Rß functioning during thymic development at or
before stage 1, whereas IL-7R may potentially function at all points
of TN development.
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As expected based on the phenotype of
IL-7R-/- and
IL-2Rß-/- mice (6, 10), all DKO
animals exhibited a substantially reduced number of splenic B cells,
and IL-2Rß/IL-7R DKO mice essentially lacked splenic NK cells
(data not shown). However, when compared with
IL-7R-/- mice, several differences in
splenic T cell cellularity were noted (Fig. 4). Both IL-2/IL7R and
IL-2Rß/IL-7R DKO mice had increased numbers of CD4 T lymphocytes
and to a lesser extent CD8 T cells. This result is similar to that
reported for older (>4 wk of age) c-/- mice
(2, 3) and suggests that this increase is due to impaired
T cell development resulting from a lack of IL-7 signaling and abnormal
peripheral CD4 T cell homeostasis due to lack of IL-2 function.
Furthermore, IL-4/IL-7R DKO mice had a somewhat lower number of
splenic CD8 T cells. The reason for this result is currently unknown
but might reflect a role for these cytokines in the survival of CD8 T
cells (24).
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IEL cell recovery was consistently reduced in
c-/-, IL-2Rß-/-,
and IL-2Rß/IL-7R DKO mice (Fig. 5),
although group variance in IEL cellularity was high in all strains
analyzed. Perhaps most striking, the analysis of IL-2Rß/IL-7R DKO
mice revealed an IEL phenotype which recapitulated that of
c-/- mice, i.e., a virtual lack of
TCR+ IEL (Fig. 5). The few viable cells isolated
from the gut preparations of either of these two strains failed to
express either TCRß, TCR, or CD8, and most likely
represent gut epithelial cell contaminants (data not shown). Thus, the
loss of IL-2Rß and IL-7R signaling abrogated IEL development.
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DKO
mice was largely comparable to wild-type C57BL/6 and
IL-7R-/- mice, respectively, demonstrating
that IL-4 does not play an obvious role in the regulation of IEL
development (Fig. 5
and Table I). As
expected, the number of nonconventional TCR CD8 IEL was
reduced in all mouse strains lacking IL-7R signaling, as well as in
IL-2Rß-/- mice. However,
IL-2-/- mice also demonstrated a marked
reduction in TCR CD8 IEL to nearly the same level as
IL-2Rß-/- mice (Figs. 5 and 6A). Moreover, both
IL-2-/- and IL-2/IL-7R DKO mice displayed a
relative decrease in nonconventional TCRß CD8 cells as
compared with wild-type C57BL/6 and IL-7R-/-
mice (Fig. 6B and Table I). These data, therefore, indicate
a role for IL-2 in the development of CD8 IEL.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DKO mice recapitulated the phenotype associated with
c-/- mice, demonstrating that impaired T
cell development is apparently accounted for by known c-dependent
cytokines. It is highly likely that the dependency on
IL-2Rß-signaling is due to IL-15 rather than IL-2, as IL-2/IL-7R
DKO mice did not display any thymic defects beyond those associated
with IL-7R-deficiency.
IL-7 appears to contribute functionally at all stages of TN thymocyte
development by providing anti-apoptotic signals (25)
and promoting the development of TCR cells (16, 17).
Support for this conclusion comes in part from the expression pattern
of IL-7R, as discussed above, and from the TN cell phenotype of
IL-7R-/- mice. The relative accumulation of
TN cells at the stage 2–3 transition, when TCR rearrangement
commences, suggests a role for IL-7 at this point in the developmental
scheme. Furthermore, the capacity of c-specific mAbs to block T cell
development from stage 3 and stage 4 pre-T cells upon intrathymic
injection (14) most likely reflects a role for IL-7 and
not IL-15 at these stages, as IL-2Rß is not detected on these cells.
IL-7R may also function at stage 1 to down-regulate NK1.1,
as we often observed detectable levels of this protein on stage 2 and 3
TN cells in IL-7R-/- single and DKO mice. As
in wild-type mice, a relatively high proportion (50%) of stage 2/3
TN cells in IL-7R-/- mice expressed
c-kit, a marker of lymphoid precursors cells, suggesting
that this finding represented a true impairment in the down-regulation
of NK1.1, rather than committed thymic NK cells with an abnormal
phenotype.
IL-15 most likely functions at the earliest points in T cell
development, as IL-2Rß expression was detected only on stage 1 pro-T
cells and others have demonstrated expression of this receptor on fetal
stem cells (26). The production of many of the TN cells
bearing a stage 1
(CD44+CD25-) phenotype
appears to be dependent on IL-15, as these cells are reduced in
IL-2Rß-/- mice, as well as in
c-/- mice. One role for IL-15 at this early
point in T lineage development is in the production of thymic-dependent
NK cells (19, 27). The relative accumulation of stage 1 TN
cells in IL-7R-/- mice is accounted for, at
least in part, by functional IL-15 signaling via IL-2Rß. This
increased proportion of stage 1 TN cells primarily represents an
increase in NK1.1+ cells. Multilineage precursors
have been identified during fetal development which express both NK1.1
and c-kit (28), and as we did not detect an
increase in c-kit+ stage 1 TN cells in
IL-7R-/- mice, it is likely that these TN
cells represent thymic NK cells.
A second role for IL-15 is to contribute to the mainstream production
of thymic T cells. Two observations support this conclusion. In this
study, we consistently detected fewer thymocytes in IL-2ß/IL-7R
DKO mice than in IL-7R-deficient mice. We also previously showed
that c-specific mAbs inhibited T cell development in irradiation
chimeras reconstituted with bone marrow precursor cells from
IL-7R-/- mice (14). This latter
effect most likely is due to a blockade of IL-15R signaling, because
this study demonstrated no role for IL-2 or IL-4 in the production of
thymic T cells, and we have previously shown no role for IL-9
(14). The function of IL-15 in thymic T cell development
may largely overlap with that of IL-7, because thymocyte number and
CD4/CD8 subset distribution is essentially normal in
IL-15R-/- mice and young
IL-2Rß-/- mice (10, 12). The
IL-7R and IL-2Rß are both expressed early in lymphoid development, as
IL-7R is expressed on bone marrow lymphoid progenitor cells
(29) and, as shown herein, on all subsets of TN cells,
permitting a potential overlap in function.
With respect to the role of c-dependent cytokines in IEL
development, two important observations were made. First, our data
clearly demonstrate a role for IL-2 in extrathymic T cell development.
There was a clear decrease in the proportion of both TCR
CD8 and TCRß CD8 IEL in mice lacking IL-2, while
conventional TCRß CD8ß IEL were largely unaffected in mice
lacking either IL-2 or IL-15 signaling. Although reductions in
TCR and CD8 IEL have been reported for older
IL-2-/- mice (30, 31), these
studies only examined colonic T lymphocytes in mice with active
autoimmune colitis, rather than the IEL from the small intestine of
young, healthy IL-2-/- mice, as in the current
study. Our data regarding a role for IL-2 in IEL development are
consistent with an additional report which examined the IEL of
gnotobiotic IL-2-/- mice (32).
These findings seem to contradict a conclusion drawn from IL-2/IL-4 DKO
mice which had been reported as having normal numbers of TCR and
CD8 IEL (13). However, this limited analysis of
IL-2/IL-4 DKO IEL did not distinguish between conventional and
nonconventional IEL subsets, and the low number of TCR and
CD8 IEL reported as "normal" in these mice (16%) may also be
interpreted as a decrease in nonconventional T cells, as the IEL of
wild-type mice are typically composed of 30–60% TCR cells.
Defects in CD8 IEL development are obvious in both
IL-2-/- mice and
IL-15R-/- mice, but are most pronounced in
IL-2Rß-deficient animals. Thus, IL-2 and IL-15 appear to function in
redundant and overlapping fashion for the development of CD8
lineage IEL. The contribution of IL-2 may be somewhat dominant over
IL-15, as the developmental defect we observed in
IL-2-/- mice was somewhat greater than that
reported for IL-15R-/- mice
(12). In any case, there are likely two separate but as
yet undefined steps in CD8 IEL development, wherein IL-2 likely
predominates in one and IL-15 in the other, to account for these
results. Furthermore, the presence of normal to increased numbers of
TCRß CD8 IEL in IL-7R-/- mice
implies that commitment to CD8 differentiation occurs before TCR
designation. Thus, in the IEL the function of IL-7/IL-7R signaling
appears to be limited to the differentiation of TCR cells.
A second striking observation noted in the IEL was the capacity of
IL-2Rß/IL-7R DKO mice to recapitulate the T cell defects of
c-/- mice, as was also shown in the thymus.
The virtual absence of all IEL subsets in IL-2Rß/IL-7R DKO mice
was somewhat remarkable, considering that conventional phenotypic
TCRß CD8ß and TCRß CD4 IEL are present in normal numbers
in IL-2-, IL-2Rß-, IL-7R-, and IL-15R-deficient mice (12, 17, 19). Thus, the simplest interpretation of this finding is
that an early lymphoid precursor redundantly requires signaling via
IL-7R or IL-2Rß to give rise to IEL of conventional phenotype. It
is difficult to rule out a role for IL-2 in the IEL at an early stage
because IL-2, like IL-15, clearly contributes to IEL development, as
discussed above. In addition, IEL of conventional phenotype were also
selectively unaffected in anti-c mAb-treated chimeric mice,
suggesting the importance of a cytokine whose activity was poorly
blocked by these Abs (15). In this regard, the
c-specific mAbs used in this study were shown to be much more potent
inhibitors of IL-7 and IL-15, than IL-2. Ultimately, the determination
of whether these precursor cells express functional IL-2R and/or IL-15R
should help resolve this issue.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas R. Malek, Department of Microbiology and Immunology, University of Miami School of Medicine, P.O. Box 016960 (R-138), Miami, FL 33101. E-mail address:
3 Abbreviations used in this paper: c, common chain; IEL, intraepithelial lymphocytes; DKO, double knockout; TN, triple negative.
Received for publication July 23, 1999. Accepted for publication September 16, 1999.
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References |
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c-dependent cytokines and receptors: regulation of T lymphocyte development and homeostasis. Crit. Rev. Immunol. 18:503.[Medline]
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chain. Proc. Natl. Acad. Sci. USA 92:377. chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521.[Medline]
-chain of cytokine receptors regulates intrathymic T cell development at multiple stages. J. Immunol. 158:2592.[Abstract]
-chain as cytokine receptor antagonists in vivo: effect on intrathymic and intestinal intraepithelial T lymphocyte development. J. Leukocyte Biol. 63:643.[Abstract]
T cell development and early thymocyte maturation in IL-7-/- mice. J. Immunol. 157:2366.[Abstract]
is essential for the development of + T cells, but not natural killer cells. J. Exp. Med. 184:289.c subunits. J. Interferon Cytokine Res. 15:447.[Medline]
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S.-K. Ye, K. Maki, H.-C. Lee, A. Ito, K. Kawai, H. Suzuki, T. W. Mak, Y.-h. Chien, T. Honjo, and K. Ikuta Differential Roles of Cytokine Receptors in the Development of Epidermal {gamma}{delta} T Cells J. Immunol., August 15, 2001; 167(4): 1929 - 1934. [Abstract] [Full Text] [PDF]
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T. Musikacharoen, T. Matsuguchi, T. Kikuchi, and Y. Yoshikai NF-{{kappa}}B and STAT5 Play Important Roles in the Regulation of Mouse Toll-Like Receptor 2 Gene Expression J. Immunol., April 1, 2001; 166(7): 4516 - 4524. [Abstract] [Full Text] [PDF]
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N. Toyama-Sorimachi, Y. Taguchi, H. Yagita, F. Kitamura, A. Kawasaki, S. Koyasu, and H. Karasuyama Mouse CD94 Participates in Qa-1-Mediated Self Recognition by NK Cells and Delivers Inhibitory Signals Independent of Ly-49 J. Immunol., March 15, 2001; 166(6): 3771 - 3779. [Abstract] [Full Text] [PDF]
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R. Ishimitsu, H. Nishimura, T. Yajima, T. Watase, H. Kawauchi, and Y. Yoshikai Overexpression of IL-15 In Vivo Enhances Tc1 Response, Which Inhibits Allergic Inflammation in a Murine Model of Asthma J. Immunol., February 1, 2001; 166(3): 1991 - 2001. [Abstract] [Full Text] [PDF]
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