By
From the Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110
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Abstract |
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CD4+ and CD8+ T cells exhibit important differences in their major effector functions. CD8+
T cells provide protection against pathogens through cytolytic activity, whereas CD4+ T cells
exert important regulatory activity through production of cytokines. However, both lineages
can produce interferon (IFN)-, which can contribute to protective immunity. Here we show
that CD4+ and CD8+ T cells differ in their regulation of IFN-
production. Both lineages require signal transducer and activator of transcription (Stat)4 activation for IFN-
induced by
interleukin (IL)-12/IL-18 signaling, but only CD4+ T cells require Stat4 for IFN-
induction
via the TCR pathway. In response to antigen, CD8+ T cells can produce IFN-
independently of IL-12, whereas CD4+ T cells require IL-12 and Stat4 activation. Thus, there is a lineage-specific requirement for Stat4 activation in antigen-induced IFN-
production based on
differences in TCR signaling between CD4+ and CD8+ T cells.
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Introduction |
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Interferon (IFN)- enhances defense against bacterial and viral pathogens (1) and is produced by both innate and adaptive immune cells, including NK cells, CD8+ T cells, and
CD4+ T cells. NK cells are an important source of IFN-
in
early infection, and can secrete IFN-
upon initial activation
(2). In contrast, CD4+ cells produce little IFN-
on primary
activation and require cytokine-dependent differentiation to
acquire this capacity (3, 4). Further, CD4+ T cells exhibit a
developmental dichotomy diverging to either an IFN-
-producing (Th1) or IL-4-producing (Th2) phenotype (5, 6). A
similar paradigm was recently extended to CD8+ T cells,
where Tc1 and Tc2 subsets develop in response to conditions that induce Th1 and Th2 subsets (7). However, unlike
Th2 cells, Tc2 cells retain the capacity for IFN-
production,
although reduced compared with Tc1 cells, and produce
quantitatively less IL-4 relative to their CD4 counterpart (7).
For CD4+ T cells, Th1/Th2 polarization involves IL-12
and IL-4 signaling via the JAK-STAT Janus kinases/signal
transducer and activator of transcription) pathway (11).
The role of IL-12 in Th1 development was established using both IL-12- and Stat4-deficient mice (12, 13, 16). IL-12 p40-deficient mice had impaired NK responses and
lower IFN- production from CD4+ T cells (16), but IFN-
secretion by LAK cells and generation of allo-specific CTL
were unimpeded. These studies suggested IL-12-independent pathways in NK cells and CTLs. Stat4-deficient mice
exhibit reduced but not absent IFN-
production (12, 13),
but the source was not apparent, since these studies used unseparated splenocytes and polyclonal activation. In sum,
these studies suggest not all cell types are entirely IL-12 and
Stat4 dependent for IFN-
production.
The TCR pathway has been considered the only physiologic stimuli for IFN- induction in CD4+ T cells. However, IL-12 and IL-18 were shown to induce IFN-
production in Th1 cells by a TCR-independent mechanism
(17). The pathways activated by TCR and IL-12/IL-18
treatment are differentially sensitive to Cyclosporin A inhibition and appear to induce IFN-
transcription through
activation of distinct sets of factors (18). Thus the requirements for Stat4 and IL-12 in IFN-
production may depend on the activating stimulus as well as the cell type.
In this study, we directly compared the CD4+ and CD8+
T cells for IL-12 and Stat4 requirements in IFN- induction through the TCR or IL-12/IL-18 pathways. We find
that CD4+ and CD8+ T cells exhibit lineage-specific differences in requiring Stat4-activation for IFN-
production. Specifically, both CD4+ and CD8+ T cells require
Stat4 in IL-12/IL-18 induction of IFN-
, but only CD4+
T cells require Stat4 for TCR induced IFN-
production.
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Materials and Methods |
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Animals.
Stat4-deficient DO11.10 TCR-transgenic mice have been described previously (12, 19). 2C TCR transgenic mice (20) were obtained from Dr. T. Hansen (Washington University, St. Louis, MO).Cytokines, Antibodies, and Other Reagents.
Recombinant human IL-2, IL-4, IL-12, and KJ1-26 (21) were used as previously described (19). Recombinant murine IL-18 (Research Diagnostics Inc.) was used at 50 ng/ml. Anti-IL-12 (TOSH) (22) and anti- IFN-T Cell Purification and Cultures.
Sorted CD4+ DO11.10 T cells (2 × 105/ml) were activated with 0.3 µM OVA peptide (OVA), IL-2, IL-12, and irradiated BALB/c splenocytes as previously described (3). In other experiments, DO11.10 splenocytes (3 × 106/ml) were activated with OVA, IL-2, IL-12 (Th1), or IL-4 (Th2) as indicated in the figure legends. CD8+ T cells were sorted from spleen and lymph node cells of 2C mice and activated (2 × 105/ml) using irradiated BALB/c splenocytes (1.5 × 106/ml). CD4+ and CD8+ T cells were sorted from spleen and lymph node cells of Stat4-deficient or wild-type mice, and stimulated (4 × 105/ml) with irradiated C57BL/6 splenocytes (4 × 106/ml), IL-2, and the indicated cytokines and antibodies.ELISA and Intracellular Cytokine Staining.
IFN- ![]() |
Results |
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Previous analyses of Stat4-deficient mice reported five- to sixfold reduced
IFN- production based in part on polyclonal cellular activation of unseparated splenocytes (12, 13). To examine the
requirement for Stat4 in antigen-specific CD4+ T cells, we
used DO11.10 TCR-transgenic mice crossed to either wild-type or Stat4-deficient backgrounds. Splenocytes from un-immunized mice were primed in vitro and induced toward
Th1 and Th2 phenotypes (4) (Fig. 1 A). As expected, wild-type DO11.10 T cells primed in the presence of IL-12
generated high levels of IFN-
upon secondary stimulation. In contrast, Stat4-deficient DO11.10 T cells primed with IL-12 generated nearly 100-fold less IFN-
, confirming that Stat4 has a significant role in CD4+ T cells for
IFN-
production.
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After in vitro priming, clonotype-positive (KJ1-26+) T
cells from wild type DO11.10 transgenic mice are predominantly CD4+. However, in Stat4-deficient mice, as much as
25% of the KJ1-26+ T cells are CD4 (Fig. 1 B) and CD8
(not shown) after in vitro priming. Double-negative T cells
have been reported to exhibit differences in Th1/Th2 regulation, with impaired Th2 development (24, 25). Thus, we
wished to assess production of IFN-
in CD4+ and CD4
T
cells using intracellular cytokine staining (Fig. 1 B). Wild-type DO11.10 T cells produced abundant intracellular IFN-
production, whereas Stat4-deficient DO11.10 T cells showed
a significantly lower percentage of IFN-
-producing cells
with lower mean fluorescence intensities relative to wild-type T cells (Fig. 1 B). Of the Stat4-deficient DO11.10 T
cells, 6% of CD4+ cells produced IFN-
, whereas 13% of
CD4
negative cells produced IFN-
, implying that in KJ1-26+ T cells, CD4+ cells are more Stat4 dependent for IFN-
production than are CD4
cells.
These and other results suggest that IFN- production
may be regulated differently in various T cell lineages (16, 26, and Carter, L.L., unpublished observations). Therefore,
we wished to compare CD4+ and CD8+ T cells from TCR-transgenic mice for their dependence on IL-12 for driving
IFN-
production (Fig. 1 C). CD8+ or CD4+ T cells were
sorted from 2C TCR-transgenic mice or DO11.10 mice, respectively, and primed with antigen in the presence of
IL-12 or anti-IL-12 antibody for 6 d, restimulated, and assessed for IFN-
production. CD4+ DO11.10 T cells produced high IFN-
when primed with IL-12, but virtually
undetectable IFN-
when primed with anti-IL-12 antibody (Fig. 1 C). In contrast, 2C CD8+ T cells produced
high levels of IFN-
even when primed in the presence of
anti-IL-12 antibody, with IFN-
production being reduced only twofold relative to cells primed with IL-12.
Thus, CD8+ T cells show significant IL-12-independent
IFN-
production, whereas CD4+ T cells do not.
In the mouse, Stat4 is uniquely activated by IL-12 (11,
27, 28). Therefore, IL-12-independent IFN- production
by CD8+ T cells suggests either that Stat4 activation is IL-12
independent or that IFN-
production is Stat4 independent. To distinguish these possibilities, we analyzed purified CD4+ and CD8+ T cells from Stat4-deficient and
wild-type BALB/c mice. T cells were primed in the presence of IL-12 with either allogeneic stimulators or plate-bound anti-CD3 and anti-CD28 (Fig. 2). When primed
and reactivated with allogeneic stimulators (Fig. 2, left),
Stat4-deficient CD4+ T cells produced very little IFN-
.
In comparison, Stat4-deficient CD8+ T cells produced significantly more IFN-
, although the level observed was reduced three- to fourfold relative to the wild-type CD8+
control. When T cells were reactivated with anti-CD3
(Fig. 2, middle), Stat4-deficient CD4+ T cells remained
poor IFN-
producers, whereas Stat4-deficient CD8+ T
cells produced IFN-
at levels similar to wild-type CD8+
controls (Fig. 2, middle). When T cells were primed with
anti-CD3/anti-CD28 and IL-12, and reactivated with anti-CD3, Stat4-deficient CD4+ T cells again produced very
low levels of IFN-
, whereas Stat4-deficient CD8+ T cells
produced high levels of IFN-
(Fig. 2, right).
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We extended these results with intracellular cytokine
staining (Fig. 3). Purified CD4+ and CD8+ T cells from
Stat4-deficient and wild-type mice were primed in the
presence of IL-12 using either APCs or anti-CD3/anti-CD28, and reactivated with APCs (Fig. 3 A) or anti-CD3
(Fig. 3 B). CD4+ T cells again showed a strict requirement
for Stat4 in IFN- production with both forms of activation. In contrast, Stat4-deficient CD8+ T cells produced
abundant IFN-
with either form of activation. With anti-CD3 treatment, equivalent percentages of Stat4-deficient and wild-type CD8+ T cells produced IFN-
, whereas
with activation by APCs, IFN-
+ Stat4-deficient CD8+ T
cells were reduced twofold. Thus, in contrast to CD4+ T
cells, CD8+ T cells show significant Stat4-independent
IFN-
production, which is most apparent with direct
TCR-mediated cellular activation.
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Since APCs can produce IL-12 and IL-18 (4, 29, 30), T
cell activation using APCs could engage both the TCR and
the IL-12/IL-18 pathway for IFN- production. Therefore, we asked if these pathways were differentially Stat4
dependent in CD4+ and CD8+ T cells (Fig. 4). Purified
CD4+ and CD8+ T cells from Stat4-deficient and wild-type mice were primed with IL-12 and allogeneic APCs
and reactivated on day 6 with either anti-CD3 or IL-12/
IL-18. In response to anti-CD3, wild-type CD4+, but not
Stat4-deficient CD4+, T cells produced IFN-
. As above,
both wild-type and Stat4-deficient CD8+ T cells produced
IFN-
. However, in response to IL-12/IL-18 treatment, both CD4+ and CD8+ Stat4-deficient T cells failed to produce IFN-
. Thus, the IL-12/IL-18 pathway for IFN-
production is strictly Stat4 dependent in both CD4+ and
CD8+ T cells. In contrast, the TCR-induced pathway for
IFN-
production is Stat4 dependent only in CD4+, and
not CD8+, T cells.
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Discussion |
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Previous observations have suggested the existence of
both IL-12-dependent and -independent pathways for
IFN- production (12, 13, 16, 31). However, since
few of these studies analyzed purified cell types, the effects
of Stat4 in specific lineages were potentially obscured. Furthermore, recent studies have demonstrated that IFN-
gene
transcription can be activated by two distinct signaling pathways, one by TCR signaling and other by IL-12 and IL-18
(18), and these pathways were not individually examined in
the previous studies. Therefore, the aim of this study was to
analyze differences between CD4+ and CD8+ T cells in their
regulation of these two pathways for IFN-
production.
In this paper, we make several new observations. First,
we show that the IL-12/IL-18 pathway for induction of
IFN- operates in CD8+ as well as CD4+ T cells. Second,
we formally demonstrate that the IL-12/IL-18 pathway
is strictly Stat4 dependent in both CD4+ and CD8+ T
cells. Third, we have identified an unexpected difference
between CD4+ and CD8+ T cells in TCR signaling. Specifically, CD4+ T cells produce IFN-
in a completely
Stat4-dependent manner, whereas CD8+ T cells are Stat4
independent for TCR-induced IFN-
production.
Two pathways are now recognized
for IFN- induction (17, 18), one via TCR-signaling and
another through IL-12 and IL-18 that acts independently
of antigen stimulation (17). The TCR- and IL-12/IL-18-
induced pathways were shown to be pharmacologically distinct and to induce different transcription factors (18). In this
study, we show that IL-12/IL-18 induction of IFN-
operates in CD8+ as well as CD4+ T cells (Fig. 4). The existence
of antigen-independent IFN-
production by previously activated T cells from both CD4 and CD8 lineage has significant implications for immune regulation. By stimulating
production of cytokines in an antigen-independent manner,
this pathway allows antigen-specific T cells to operate like
innate immune cells. The Stat4-dependence of the IL-12/
IL-18-induced pathway in both CD4+ and CD8+ lineages
suggest a common IFN-
regulatory mechanism.
In contrast to IL-12/IL-18-
induced IFN-, TCR-induced signaling revealed a striking
difference in the requirement for Stat4 between CD4+ and
CD8+ T cells. Unseparated Stat4-deficient splenocytes displayed a partial reduction in IFN-
production in previous
studies (12, 13), whereas pure populations of CD4+ T cells
show a much more stringent requirement for Stat4 (Fig. 1 A).
In contrast, Stat4-deficient CD8+ T cells generated abundant IFN-
particularly when activated through the TCR.
When CD8+ T cells were activated using APCs, a partial
loss of IFN-
production was observed in Stat4-deficient
CD8+ T cells relative to wild-type controls (Figs. 2, left,
and 3 A), suggesting that activation with APCs engages
both TCR (Stat4-independent) and IL-12/IL-18 (Stat4-dependent) pathways. Activation of CD8+ T cells using
anti-CD3 restricts activation to the TCR (Stat4-independent) pathway, resulting in equivalent levels of IFN-
production by Stat4-deficient and wild-type CD8+ T cells.
Distinct regulation of IFN-
gene activation between CD4+ and CD8+ T cells has previously been suggested
(26). A Stat4-independent mechanism for IFN-
production development has recently been described (34), but as it
operated only in the absence of Stat6 and in CD4+ T cells,
it is distinct from the pathway described here.
Differences in TCR signaling between CD4+ and CD8+
lineages could reside at several levels. First, CD4+ and
CD8+ T cells may differ in expression of signaling components downstream of the TCR. For example, certain mitogen-activated protein (MAP) kinases implicated in IFN-
induction (35, 36) could be differentially expressed or activated in CD4+ versus CD8+ T cells, being Stat4 dependent
only in CD4+ T cells. Second, chromatin accessibility of
the IFN-
gene may differ between primary CD4+ and
CD8+ lineages. In this model, the IFN-
gene would be
accessible to TCR-induced factors independently of Stat4
in CD8+ T cells, but not in CD4+ T cells. However, IFN-
chromatin structure in CD4+ versus CD8+ T cells has not
yet been compared. Finally, coreceptor signaling could account for the present observations. CD8 may provide a signal that bypasses a Stat4 requirement in IFN-
production, or conversely CD4 may provide a signal imposing such a requirement. Indeed, differences between coreceptor association with src family kinase Lck have been reported (37),
and lack of CD4 expression impairs Th2 responses (24, 25).
In summary, the study presented here makes the first distinction between CD4+ and CD8+ T cells for the role of
Stat4 in regulation of IFN- expression. Given the importance of IFN-
in responses to pathogens and in autoimmune processes, it will be important to determine the basis of these lineage-specific differences in the Stat4-requirement for IFN-
gene regulation.
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Footnotes |
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Address correspondence to Kenneth M. Murphy, Department of Pathology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Phone: 314-362-2009; Fax: 314-747-4888; E-mail: murphy{at}immunology.wustl.edu
Received for publication 11 December 1998 and in revised form 10 February 1999.
We thank Debbie Wyman for excellent cell sorting.
This work was supported by National Institutes of Health grants AI34580, AIDK39676, and JDF995012. L.L. Carter is an Associate of the Howard Hughes Medical Institute. K.M. Murphy is an Associate Investigator of the Howard Hughes Medical Institute.
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