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Cutting Edge: The Related Molecules CD28 and Inducible Costimulator Deliver Both Unique and Complementary Signals Required for Optimal T Cell Activation

Department of Biology, Inflammation Division, Millennium Pharmaceuticals, Cambridge, MA 02139

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Optimal T cell activation requires engagement of CD28 with its counterligands B7-1 and B7-2. Inducible costimulator (ICOS) is the third member of the CD28/CTLA4 family that binds a B7-like protein, B7RP-1. Administration of ICOS-Ig attenuates T cell expansion following superantigen (SAg) administration, but fails to regulate either peripheral deletion or anergy induction. ICOS-Ig, but not CTLA4-Ig, uniquely regulates SAg-induced TNF- production, whereas IL-2 secretion is modulated by CTLA4-Ig, but not ICOS-Ig. In contrast, both ICOS and CD28 are required for complete attenuation of IL-4 production. Our data suggest that ICOS and CD28 regulate T cell expansion and that ligation of either CD28 or ICOS can either uniquely regulate cytokine production (IL-2/TNF-) or synergize for optimal cytokine production (IL-4) after SAg administration.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
T cell proliferation, differentiation, peripheral deletion, and anergy are regulated by signals delivered through not only the TCR, but also through cytokines and costimulatory molecules (1). The most widely studied costimulatory signal delivered to resting T cells occurs upon CD28 engagement by B7 molecules (2, 3). Mice deficient in CD28 show strong impairment of proliferation in vitro after stimulation with anti-TCR Abs, allostimulation, and specific Ags (4, 5, 6). In contrast to CD28, the second member of this family of molecules, CTLA4, delivers a negative signal to the activated T cell, opposing CD28-mediated costimulation (7). The importance of this pathway is illustrated in mice deficient in CTLA4 that exhibit profound lymphoproliferative defects (8). Recently, the third member of the family, inducible costimulator (ICOS),² has been identified (9, 10). Similar to CTLA4, ICOS is expressed only upon activation, but facilitates T cell proliferation and the secretion of IL-4, IL-10 and IFN-, but not IL-2 (9, 11). Interestingly, ICOS has been reported to deliver a signal independent of CD28 for cytokine production and proliferation in vitro (10). However, the relative role of ICOS and CD28 in the regulation of T cell function in vivo remains largely unexplored.

Superantigens (SAgs) are toxins secreted by infectious microorganisms that bind to MHC class II molecules on APC and interact with both CD4⁺ and CD8⁺ T cells bearing the appropriate TCR V-chain (12, 13, 14, 15, 16, 17). This interaction causes a strong activation of all T lymphocytes expressing SAg-specific V elements. In mice, the bacterial SAg Staphylococcus aureus enterotoxin B (SEB) elicits an initial cytokine secretion and clonal expansion of spleen and lymph node V8⁺ T cells followed by a partial clonal deletion of this leukocyte type via apoptosis. The remaining reactive V8⁺ T cells reach a state of anergy or unresponsiveness that can persist for several weeks (18, 19, 20, 21, 22, 23, 24, 25, 26, 27). A series of studies in recent years using the chimeric soluble CTLA4-Ig constant region fusion protein (CTLA4-Ig), anti-CD28 mAb Fab, or mice genetically deficient for CD28 (28, 29) have shown that costimulation through CD28 is critical for clonal expansion and cytokine production after SEB administration. In the present series of experiments, we have used this well characterized system to investigate the contribution of ICOS and the relative importance of this new pathway vs the series of events elicited by the interaction of CD28 and B7 molecules using either the competitive inhibitor of CD28/CTLA4 signaling, CTLA4-Ig, or the soluble ICOS Ig.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mice and in vivo treatment

Six-week-old BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained in a specific pathogen-free mouse facility (Millennium Pharmaceuticals, Cambridge, MA). Mice received one dose of 50 µg/mouse of SEB (Sigma, St. Louis, MO) in a single i.v. injection on day 0. Control littermates were injected with an identical volume (200 µl) of PBS. For the blocking experiments, mice also received 100 µg/mouse of ICOS-Ig or CTLA4-Ig. Fusion proteins were administered i.p. 90 min before SAg administration on days 0 and 2 for the experimental group of mice sacrificed on day 3; and on days 0, 2, 4, 6, and 8 for the experimental group of mice sacrificed on day 10. Human Ig (100 µg/mouse) was used as an appropriate control.

Immunofluorescence analysis

Spleen and lymph node monocellular suspensions were subjected to hypotonic erythrocyte lysis, washed, and then stained using mAb directed against CD4 (GK1.5), CD8 (53-6.7), V6 (RR4-7), and V8 (F23.1) obtained from PharMingen (San Diego, CA). The Abs anti-CD4 and anti-CD8 were PE labeled, and anti-V6 and anti-V8 were FITC labeled. Quantitative fluorometric analysis was performed on a FACScaliber instrument (Becton Dickinson, Mountain View, CA).

To obtain the absolute number of spleen or lymph node CD4⁺V8⁺ and CD8⁺V8⁺ T lymphocytes, the percentages of these cell types determined by flow cytometry were multiplied by the total number of cells recovered from the spleen or lymph node, respectively.

ICOS-Ig and CTLA4-Ig generation

ICOS-Ig was generated as described previously (11). CTLA4-Ig was obtained from Chimerigen (Allston, MA).

Culture conditions

Triplicates of 1.5 x 10⁵ or 3 x 10⁵ spleen cells were cultured for 3 days in medium (200 µl/well of RPMI 1640 supplemented with 10% FCS, 50 µM 2-ME, 10 nM HEPES, 200 mM L-glutamine, 10 U/ml penicillin, and 100 µg/ml streptomycin) supplemented with 20 µg/ml SEB or 3 µg/ml Con A. For blocking experiments in vitro, cells were preincubated for 2 h with different concentrations (0, 5, 50, or 100 µg/ml) of either ICOS-Ig, CTLA4-Ig, or human Ig and then stimulated with SEB (20 µg/ml) for 72 h. For assessment of proliferation, cells were harvested after an 8-h pulse labeled with 1 µCi [³H]thymidine (Amersham, Little Chalfont, U.K.).

Cytokine measurement

Blood was collected at 1, 1.5, or 2 h after enterotoxin challenge. Serial dilutions of serum samples were assayed using commercial ELISA kits for TNF-, IFN-, IL-2, IL-4, and IL-10 (Endogen, Boston, MA).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The response of peripheral T lymphocytes in BALB/c mice to the i.v. administration of SEB consists of 1) a rapid cytokine production in the serum, which peaks 90–120 min after SEB injection; 2) a transient proliferative expansion of CD4⁺V8⁺ and CD8⁺V8⁺ T cells, which reaches a maximum level at 3–4 days following SEB treatment; and 3) a deletion phase of mature V8⁺ lymphocytes via apoptosis, which is clearly present 10 days after SEB injection and lasts over 30 days (16, 19, 20, 22, 23, 24, 30, 31, 32). The surviving SEB-specific V8⁺ cells in vivo are anergic as assessed by their low proliferative response to a second enterotoxin stimulation in vitro (16, 19, 20, 22, 24).

Effect of ICOS on SEB-induced V8⁺ T cell proliferation

On day 3, SEB treatment resulted in 2-fold and 5-fold increases in the total number of peripheral CD4⁺V8⁺ and CD8⁺V8⁺ T cells, respectively, when compared with that observed in PBS-treated controls (Fig. 1, A and B). The size of the peripheral V8⁺ T cell population from PBS-treated mice is not different from that of PBS+hIg-, PBS+ICOS-Ig-, or PBS+CTLA4-Ig-treated littermates, indicating that the administration of the fusion proteins alone does not have any detectable effect on cell numbers (data not shown). However, administration of ICOS-Ig (100 µg/mouse) reduces the expansion of both CD4⁺ and CD8⁺ V8⁺ T cells in response to SEB by 70% in both secondary lymphoid tissues (Fig. 1, A and B). The suppression of T cell expansion was comparable in magnitude to that observed using CTLA4-Ig. These data support recent work in CD28-deficient mice or using CD28 mAbs that T cell expansion requires CD28 engagement (29, 33). Administration of both CTLA4-Ig together with ICOS-Ig failed to further suppress T cell expansion (data not shown). No significant responses of V6⁺ T cells to SEB in control mice or experimental littermates were detected (data not shown) indicating the specificity of SEB for V8⁺ T lymphocytes.

View larger version (20K): [in this window] [in a new window]   FIGURE 1. Effect of SEB on the clonal expansion of peripheral V8+ T cells following ICOS-Ig and CTLA4-Ig administration. Mice received a single i.v. injection of SEB, and on day 3 the absolute number of spleen (A) or lymph node (B) CD4+ V8+ (black circles) or CD8+ V8+ T cells (gray circles) was determined by flow cytometry as described in Materials and Methods. ICOS-Ig or CTLA4-Ig was administered i.p. on days 0 and 2. Each dot represents a single mouse, and each bar represents the mean of each experimental or control group. Open symbols indicate PBS-treated control littermates. *, A significant difference between control and test group of mice was determined using Student’s t test (p < 0,001). C, SEB-induced V8+ T cell proliferation in vitro following ICOS-Ig or CTLA4-Ig administration. Spleen cells from untreated mice (0.5 x 106/well) were incubated for 2 h with either ICOS-Ig (), CTLA4-Ig (), or hIg (•) at the indicated concentrations. SEB (20 µg/ml) was added to all of the wells but those control wells containing medium (). Proliferation assessment was determined after an 8-h pulse label with 1 µCi of [3H]thymidine on 48-h microtiter well cultures.

Effect of ICOS on SEB-induced V8⁺ T cell clonal deletion

Clonal size can be regulated either by depletion of Ag-stimulated cells or by anergy induction. CD28 has been demonstrated to provide an anti-apoptotic signal via the up-regulation of BCL-xL (34, 35) and at least in part, through the stabilization of IL-2 mRNA, to support T cell expansion (36). However, despite the suboptimal proliferation of peripheral CD4⁺V8⁺ and CD8⁺V8⁺ T cells detected in SEB-treated mice following either ICOS-Ig or CTLA4-Ig administration, these lymphocytic populations were reduced during the enterotoxin-driven deletion phase as much as the same populations in the SEB-treated control littermates (data not shown). This indicates that neither ICOS- nor CD28-mediated signals regulate clonal deletion in response to SEB and supports the observation that responsive cells undergo depletion in CD28-deficient mice (29).

Effect of ICOS on SEB-induced V8⁺ T cell anergy

The V8⁺ T lymphocytes that have not been eliminated by apoptosis in vivo 10 days after the single i.v. administration of SEB are anergic. Subsequently, these cells show a very low proliferative response in vitro to a second restimulation with the enterotoxin (18, 19, 20, 21, 22, 23, 24, 25, 26, 27). To determine whether costimulatory signals mediated by ICOS are required for the induction of V8⁺ T cell anergy in response to SEB, the proliferative response to SEB in vitro of splenocytes from ICOS-Ig-treated mice after SEB priming in vivo was evaluated. As expected, spleen V8⁺ T cells from SEB-treated mice failed to proliferate to the enterotoxin in vitro (Fig. 2A). Whereas CTLA4-Ig administration in vivo was able to significantly reduce SEB-induced V8⁺ T cell anergy, ICOS-Ig did not show any effect on the impairment of these cells to mount a proliferative response upon SEB restimulation (Fig. 2A). An increase in the dose of SEB (25 or 50 µg/ml) did not modify the suboptimal T cell activation observed with lower doses (data not shown). Splenocytes from mice treated with either CTLA-4Ig or ICOS-Ig show a normal response to Con A, indicating the specificity of the V8⁺ T cell anergic response to SEB (Fig. 2B). These data contrast to that observed in CD28-deficient mice, which rapidly undergo anergy induction that can be in part reversed by IL-2 administration (29). However, mice transgenic for CTLA4-Ig are also protected from anergy induction. Thus it is likely that this is a consequence of blockade of CTLA4/B7 signaling, rather than an extinction of a CD28-driven response. Indeed, in recent years it has been shown that tolerance induction is an active process of signaling through CTLA4, rather than a process that occurs as a lack of CD28-mediated costimulation (37). These data also illustrate an important confounding issue in using CTLA4-Ig, which inhibits both a positive and a negative signal; additional experiments are required using neutralizing CD28, CTLA4, and ICOS mAbs to further delineate the precise contribution of these three related family members to anergy induction.

View larger version (20K): [in this window] [in a new window]   FIGURE 2. SEB-induced anergy of spleen T cells following ICOS-Ig and CTLA4-Ig administration. Splenocytes were recovered from PBS-injected control mice (), SEB-primed mice (•), SEB+ICOS-Ig-treated mice (), or SEB+CTLA4-Ig-treated mice () 10 days after enterotoxin administration. ICOS-Ig or CTLA4-Ig was administered i.p. on days 0, 2, 4, 6, and 8. Cell proliferation was determined after an 8-h pulse with 1 µCi [3H]thymidine culturing at the indicated cell densities in microtiter wells containing SEB for 72 h (A) or Con A (B) for 48 h.

Cytokine production after SAg administration is a consequence of T cell-derived stimulation (25, 38). We next investigated whether CD28 and ICOS would also deliver comparable signals required for cytokine production. CD28-mediated costimulation is critical for SEB-induced early secretion of IL-2 (Fig. 3); however, by 2 h post SEB administration, IL-2 production is comparable in both control Ig- and CTLA4-Ig-treated mice (Fig. 3). Administration of ICOS-Ig had no significant effect on IL-2 production and did not synergize with CTLA4-Ig for additional suppression of IL-2 secretion (Fig. 3). In contrast, ICOS, but not CD28, delivered an important signal for TNF- secretion (Fig. 3). Similar to IL-2, no synergistic effects between ICOS and CD28 were observable (Fig. 3). These results differ from data using CD28-deficient mice, which exhibit a marked protection from repeated peritoneal administrations of Toxin Shock Syndrome toxin-1 (TSST-1), which is a consequence of abrogated TNF- production (39). Likewise, SEB-induced TNF- production was partially protected by anti-B7-2, but not B7-1 blockade (40). The precise reasons for these differences are at present unknown, although different toxins and routes of administration might use different signals. IFN- production was completely inhibited by CTLA4-Ig, although ICOS-Ig alone reduced IFN- levels by 50% 2 h post SEB administration (Fig. 3). Finally, CD28 signaling was important for IL-4 production, whereas ICOS-Ig administration alone was ineffective (Fig. 3). However, unlike IL-2, IFN-, and TNF-, the combination of CD28 and ICOS blockade completely inhibited IL-4 production (Fig. 3). Thus CD28 delivers signals preferential for IL-2 and IFN-, ICOS signals for TNF-, whereas CD28 and ICOS synergize for complete inhibition of IL-4 production in response to SEB. These data support our recent findings after infection with the nematode Nippostrongylus brazileneis, where ICOS regulates T cell expansion and effector cytokine production (41).

View larger version (32K): [in this window] [in a new window]   FIGURE 3. Effect of ICOS-Ig or CTLA4-Ig administration on serum cytokine production following SEB stimulation. The systemic release of the mentioned cytokines was measured after a single i.v. dose of SEB. Mice subjected to the indicated treatments were bled from the retro-orbital plexus at 1, 1.5, or 2 h after challenge with SEB. Within each group, sera from four mice were measured by ELISA in duplicates.

	Acknowledgments

 
We thank Dr. M. Kopf and Dr. M. Hodge for the critical reading of this manuscript. We also thank Kevin Goodbout for purification of ICOS-Ig, and Chris Groves for advice on FACS analysis. We are indebted to Jane Tian and Steven Manning for their excellent contribution on this work.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Anthony J. Coyle, Department of Biology, Inflammation Division, Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139.

² Abbreviations used in this paper: ICOS, inducible costimulator; SAg, superantigen; SEB, Staphylococcus aureus enterotoxin B.

Received for publication September 5, 2000. Accepted for publication October 12, 2000.

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