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* Diabetes Center and Department of Medicine, University of California, San Francisco, CA 94143;
Deparment of Rheumatology, Children’s Hospital Medical Center, Cincinnati, OH 45229;
Department of Surgery, Section of Transplantation and
Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, IL 60637;
¶ Abramson Research Institute, University of Pennsylvania Cancer Center, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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portion of the TCR complex, has been used clinically for almost two decades to reverse steroid-resistant acute graft rejection, and it remains the only anti-CD3 mAb approved for use in clinical transplantation (1). In a murine autoimmune diabetes model, anti-CD3 mAb administration remains one of the few therapies that reverse active diabetes (2, 3). Previous studies in a murine model for OKT3 treatment, using the hamster Ab 145-2C11, have suggested that anti-CD3 mAb treatment results in profound inhibition of T cell responses (4). Although we hypothesized that down-modulation of the TCR, T cell apoptosis, and the induction of unresponsiveness all potentially contributed to immunosuppression in this setting, the mechanisms by which anti-CD3 induces T cell tolerance remains unclear. T cell apoptosis has been studied extensively in vitro and in vivo (5, 6). Biochemically, apoptosis can occur through one of the two pathways: the death receptor (caspase 8)-initiated pathway and the mitochondria (caspase 9)-initiated pathway. Repeated stimulation of T cells induces T cells to die through the death receptor pathway, and this form of T cell apoptosis is often referred to as activation-induced cell death (AICD).4 T cell AICD is largely initiated by Fas and Fas ligand interactions and is not protected by antiapoptotic proteins, Bcl-xL and Bcl-2 (7, 8). The role of CD28 costimulation in the AICD is complex and not completely clear (9). During the sensitization phase, CD28 has been shown to either enhance AICD by increasing IL-2 production (10, 11) or to protect against AICD through induction of survival factors (12, 13).
Clear evidence shows that T cell apoptosis can occur independent of Fas and Fas-related death receptors. Fas-independent T cell death can be triggered by a variety of noxious stimuli such as growth factor deprivation, glucocorticoids, gamma irradiation, and reactive oxygen radicals (ROS) (14). One common feature of T cell death induced by these treatments is the loss of mitochondria transmembrane potential, release of apoptosis-promoting factors, and activation of caspase 9. A recent report demonstrates that this form of stress-induced cell death (SICD) is likely mediated by proapoptotic protein Bim and that the increased ratio of Bim to the antiapoptotic protein Bcl-xL results in apoptosis (15). Bcl-xL protects cells against SICD by maintaining mitochondrial integrity (16). Signaling through CD28 induces Bcl-xL expression and protects T cells from death during the waning phase of primary responses (17, 18).
T cell hyporesponsiveness, or anergy, has also been recognized as a major mechanism of peripheral tolerance, and both CD28 and CTLA-4 have been implicated in the development of T cell anergy. When T cells are stimulated via their TCRs, the presence or absence of the CD28 costimulatory signal determines whether the T cells engage in a productive or abortive response. Signaling through TCR without CD28 ligation induces profound T cell unresponsiveness in T cell clones in vitro (19). However, the surprising immune competence of CD28-deficient animals raises the question of whether the in vitro model of CD28-deficient clonal anergy applies to in vivo situations. The ability of CTLA-4Ig (a fusion molecule that blocks CD28-B7 interactions) to prolong graft survival and prevent autoimmune diseases has been interpreted as a form of in vivo anergy. Yet when cells from CTLA-4Ig-treated animals have been re-examined in vitro, they demonstrate unimpaired responsiveness (20). It has been postulated that rather than inducing anergy in vivo, TCR stimulation in the absence of CD28 either fails to "prime" T cells (and thus T cells may respond as naive T cells) or leads to T cell death (21). By comparison, CTLA-4 can antagonize TCR signaling (22), block cell cycle progression (23), compete with CD28 for B7 molecules, and induce Th deviation (24, 25). In this regard, CTLA-4 has been shown to play an obligatory role in the induction and maintenance of anergy in many model systems. For example, i.v. injection of a large dose of soluble antigenic peptide (21, 23) or Ag coupled to chemically fixed APC (26) induces Ag-specific hyporesponsiveness that is dependent on CTLA-4.
In this study, we examined the mechanism of anti-CD3-mediated immunosuppression in vivo. Anti-CD3 mAb-induced T cell depletion was independent of Fas but controlled by CD28-dependent regulation of Bcl-xL expression. In fact, transgenic expression of Bcl-xL in T cells completely blocked T cell depletion and severely compromised anti-CD3-induced cardiac allograft survival. In addition, anti-CD3 was shown to promote T cell unresponsiveness. This in vivo anergy was more pronounced in the absence of CD28 and B7-2 interaction. Thus, our results demonstrate that multiple pathways contribute to the profound immunosuppressive activity of anti-CD3 therapy. Furthermore, T cell depletion, not T cell anergy, appears to be the critical component to anti-CD3-induced immunosuppression in vivo.
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Materials and Methods |
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Wild-type C57BL/6 mice were purchased from Frederick Cancer Research Institute Laboratories (Frederick, MD). CD28-deficient and Bcl-xL-transgenic mice on the C57BL/6 background were bred and maintained at the University of Chicago (Chicago, IL). Hamster anti-mouse CD3 (145-2C11), hamster anti-mouse B7-1 (16-10-A1), and rat anti-mouse B7-2 (GL-1) were purified from hybridoma culture supernatant and used for in vivo treatments. Hamster anti-mouse CTLA-4 (4F10) mAbs were purified and Fab were used for in vivo treatment. Fluorochrome-conjugated anti-mouse CD4, CD8, Thy1, CD69, IL-2R
were purchased from Southern Biotechnology Associates (Birmingham, AL).
In vitro responsiveness assay
Mice were treated with 100 µg or 200 µg anti-CD3. On day 12 after injection, splenocytes were harvested and anti-CD3-treated samples were enriched for T cells by anti-heat stable Ag plus complement depletion of B cells. The samples were then rested for 16–48 h to allow re-expression of TCR, and then 100,000 T cells were plated with 200,000 fresh APC (irradiated, T-depleted splenocytes) in round-bottom 96-well plates with a 10-fold dilution of anti-CD3 mAb. At 48 h, cultures were pulsed with thymidine overnight, then harvested and counted. Similar proliferation results were obtained without allowing for an in vitro rest period.
FACS analysis of Bcl-xL expression
To analyze Bcl-xL expression after in vitro stimulation, splenocytes from wild-type or CD28-/- mice were cultured overnight at 5 x 106 cells/2 ml of culture in the presence or absence of 1 µg/ml 2C11. At 24 h, the cultured cells were stained with anti-CD4 or CD8 PE, fixed, and permeabilized with saponin for intracellular staining with anti-Bcl-xL FITC or a negative control IgG3 FITC. To determine the Bcl-xL expression level after in vivo stimulation, mice were injected with 200 µg anti-CD3 and then at 24 h after injection, spleen cells were harvested and prepared for FACS as described above.
Cardiac allograft transplantation
The surgery was performed as described elsewhere (27). Briefly, cardiac allografts were transplanted in the abdominal cavity by anastomosing the aorta and pulmonary artery of the graft end-to-side with the recipient’s aorta and vena cava, respectively. Graft function was assessed daily by palpation. The day of rejection was defined as the last day of detection of a palpable heartbeat. Graft rejection was verified in selected cases by autopsy and pathologic examination. Loss of heart graft function within 48 h of transplant was considered a technical failure and those cases were excluded from further analysis.
Statistical analyses
Student’s t test was used to analyze the in vivo T cell depletion data and in vitro proliferation data. Graft survival data were analyzed using the method of Kaplan-Meier with a log rank p test with the aid of Prism software (GraphPad, San Diego, CA).
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Results |
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Anti-CD3 treatment results in the depletion of most T cells from secondary lymphoid organs within 2 wk after treatment (Fig. 1a). Since anti-CD3 also induces massive activation of T cells in vivo, the T cell depletion could be attributed to either AICD or extravasation of T cells to nonlymphoid tissues. To address these two possibilities, T cell depletion following anti-CD3 mAb therapy of wild-type B6 vs Fas-deficient lpr mice was compared. In contrast to expectations and findings of several laboratories using Ag injection (28, 29, 30, 31), anti-CD3 induced equal levels of T cell depletion in lpr and wild-type controls (Fig. 1a). Interestingly, these results are more similar to those observed following injection of the superantigen staphylococcal enterotoxin B (14). Thus, it would appear that the in vivo T cell depletion induced by anti-CD3 is not typical AICD. To further address the process of depletion, transgenic mice constitutively expressing Bcl-xL in T cells were treated with the depleting regimen. There was no apparent T cell depletion 2 wk after anti-CD3 treatment (Fig. 1b), suggesting that anti-CD3 therapy did induce apoptosis via a mitochondria-dependent mechanism.
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Previous studies have suggested that conventional AICD depends on CD28-mediated T cell costimulation (10, 11). In contrast, signaling through CD28 induces Bcl-xL expression in vitro, which would be expected to protect T cells from undergoing apoptosis in this model. Thus, we examined whether the CD28 engagement regulated the apoptotic process in anti-CD3-treated mice. In repeated experiments, anti-CD3 treatment of CD28-/- mice resulted in a 2- to 4-fold greater depletion of the CD4+ T cells as compared with wild-type mice (Fig. 2a). It should be noted that T cell depletion was never complete in CD28-/- mice, suggesting that CD28 was not absolutely required for T cell survival following anti-CD3 challenge. This residual survival was possibly due to a resistant memory T cell subset in these animals. The difference in T cell depletion between CD28-/- and wild-type mice suggests that in vivo anti-CD3 treatment in wild-type mice involves CD28 engagement, which may promote T cell survival. To test this hypothesis, up-regulation of the CD28/IL-2-sensitive activation marker IL-2R was examined 24 h following injection (Fig. 2b). A significant, at least 8-fold, increase in CD25 expression was observed in wild-type T cells from treated animals. In contrast, T cells from CD28-/- mice up-regulated IL-2R to a lesser extent (2- to 4-fold). The result of the anti-CD3 therapy was distinct in the CD8+ subset. The degree of CD8+ T cell depletion was comparable between wild-type and CD28-/- mice. This is not due to lack of CD28 engagement on CD8 cells, since CD25 expression is 2-fold higher in wild-type mice than that in CD28-/- mice after anti-CD3 treatment. Together these results suggest that CD28 ligation selectively promotes survival of the naive CD4+ T cell subset following in vivo administration of anti-CD3, consistent with a greater role for the CD28 costimulatory pathway in CD4+ vs CD8+ T cells.
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The most likely explanation for the increased survival in CD28-sufficient mice is the role of CD28 ligation in up-regulating the antiapoptotic molecule Bcl-xL in vivo, similar to what has been observed in vitro. Thus, Bcl-xL expression in CD4+ and CD8+ T cells from wild-type and CD28-/- mice was examined after in vitro or in vivo exposure to anti-CD3 (Fig. 3). Following anti-CD3 treatment, CD28-/- CD4+ T cells showed a selective defect in up-regulating Bcl-xL both in vitro (Fig. 3, left panel) and in vivo (Fig. 3, right panel) when compared with wild-type controls. Defects in Bcl-xL induction in CD28-/- CD8+ T cells were less pronounced, correlating with a lack of enhanced CD8+ T cell depletion and the diminished role of CD28 engagement in CD8+ T cell survival in these mice.
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The increased expression of IL-2R and Bcl-xL in wild-type CD4+ T cells shown above suggested that at least some of these T cells ligated their CD28 molecules following anti-CD3 stimulation, which might protect them from anergy induction. Thus, we examined the responsiveness of the treated T cells isolated from CD28-deficient animals. T cells from anti-CD3-treated wild-type B6 mice were hyporesponsive to in vitro restimulation (Fig. 4a). This was not due to loss of TCR expression as the T cells were rested ex vivo overnight to ensure adequate receptor re-expression before in vitro culture. Interestingly, anti-CD3-treated CD28-/- T cells displayed even less proliferative capacity, consistent with the hypothesis that these cells were more efficiently anergized in vivo (Fig. 4b). However, previous studies (confirmed herein) have shown that CD28-/- T cells proliferated less well in vitro as compared with their wild-type counterparts due to the rapid apoptosis of these cells. Thus, it was possible that the T cells recovered from these CD28-/- mice were committed to die upon second encounter with Ag in vitro due to the lack of Bcl-xL up-regulation. T cells from CD28-/- or CD28-/- Bcl-xL-transgenic mice treated with anti-CD3 demonstrated more profound hyporesponsiveness when compared with that observed in either wild-type or Bcl-xL-transgenic mice (Fig. 4, compare a and b, c and d). Together these results indicate that anti-CD3 mAb treatment results in profound hyporesponsiveness in vivo that is enhanced in the absence of CD28 ligation.
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Engagement of TCR without simultaneous ligation of CD28 leads to clonal anergy in vitro (19). In this study, we show that this in vitro phenomenon can occur in vivo. We next examined the role of CD28 ligands B7-1 and B7-2 in regulating CD3-induced T cell hyporesponsiveness in vivo. Wild-type mice were treated with anti-B7-1 or anti-B7-2 mAbs at the time of anti-CD3 injection. At 12 days after anti-CD3 injection, responsiveness was evaluated by restimulation with anti-CD3 mAbs in vitro. Anti-B7-1 did not have any effect on anti-CD3 mAb-induced hyporesponsiveness (Fig. 5a, compare to Fig. 4a). In contrast, anti-B7-2 treatment led to more profound hyporesponsiveness induced by anti-CD3 mAbs similar to that observed in CD28-/- mice (Fig. 5b, compare to Figs. 5a and 4b). Moreover, unlike other models of in vivo hyporesponsiveness (21, 23), the hyporesponsiveness observed after anti-CD3 treatment appeared to be independent of CTLA-4 as blocking CTLA-4 during in vivo anti-CD3 treatment did not affect the depth of T cell hyporesponsiveness (Fig. 5c, compare to Fig. 4a). Thus, taken together, these results suggest that CD28 interacts with B7-2 in vivo to reduce T cell hyporesponsiveness after anti-CD3 treatment, while CTLA-4 does not play a role.
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The previous results demonstrate that anti-CD3 therapy triggers multiple mechanisms to block or suppress T cell responsiveness in vivo. However, the key question remains as to which pathway is critical to the enhanced graft survival observed in anti-CD3-treated mice. The selective block of T cell depletion by Bcl-xL overexpression provided us with a model system to examine the relative contributions of T cell depletion vs unresponsiveness following anti-CD3-induced immunosuppression in vivo. Bcl-xL-transgenic mice or wild-type control mice were grafted with fully allogeneic BALB/c hearts and treated with anti-CD3 mAbs. In this model, rejection of allogeneic cardiac grafts has been shown to be mediated by CD4+ cells while CD8+ plays a minimal role (32). Untreated Bcl-xL- transgenic and wild-type mice rejected their hearts with comparable kinetics (15 and 14 days, respectively, Fig. 6). Anti-CD3 treatment prolonged graft survival indefinitely (>100 days) in wild-type mice. However, in the Bcl-xL mice, anti-CD3 treatment was significantly less effective, prolonging graft survival only transiently (21 days average survival). Thus, even though the anti-CD3 mAbs induced T cell hyporesponsiveness in Bcl-xL-transgenic mice, cell death was critical for anti-CD3-mediated long-term immunosuppression.
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Discussion |
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The lack of Fas involvement in anti-CD3-induced T cell depletion and its complete protection by constitutive overexpression of Bcl-xL was striking and unexpected. Many previous studies using nominal Ag (8, 28, 33) or superantigen (29, 30, 31, 34, 35) have shown dependence on Fas/Fas ligand for AICD. The cell death observed after anti-CD3 treatment bears great resemblance to that induced by in vivo injection of a large dose of Ag superantigen, which is mediated by ROS (14). In that system, potent T cell activation by superantigen induces ROS production, which in turn causes loss of mitochondrial transmembrane potential and activation of caspase 9. It has been demonstrated recently that the cell death induced by superantigen was the result of loss of balance between Bcl-xL and the proapoptotic protein Bim (15). Taken together, our data suggest that in vivo T cell depletion induced by anti-CD3 is mediated by SICD rather than AICD. It is not clear why anti-CD3 and some superantigen treatment protocols trigger SICD whereas others preferentially induce AICD. One possibility is that anti-CD3 mAbs are more potent TCR agonists, therefore more effective at inducing ROS. Indeed, large single-dose superantigen has been shown to elicit SICD (14), whereas small increment doses of the same superantigen induced AICD (29, 30, 31, 34, 35). However, it is equally possible that anti-CD3 mAbs induce a qualitatively different signal in T cells that induce them to die of SICD. In this regard, it has been shown that anti-CD3 and Ag induce biochemically distinct signals in T cells (36). It is important to distinguish different forms of cell death when one considers combination treatment to achieve better immunosuppression. For example, IL-2 can enhance AICD, but will protect against SICD. We have shown that lack of CD28 ligation leads to enhanced T cell death by attenuating Bcl-xL up-regulation in vivo. Therefore, CD28 blockade may help to improve the efficacy of anti-CD3 therapy.
In response to anti-CD3 mAbs, CD28-/- T mice demonstrated increased CD4+ T cell death, decreased IL-2R expression, and more profound hyporesponsiveness. Thus, in normal CD28-competent mice, anti-CD3 treatment promotes both signal 1 and CD28-mediated signal 2. The signaling through CD28 appears to regulate both T cell depletion and unresponsiveness during anti-CD3 treatment. Signaling through TCR in the absence of CD28 ligation leads to T cell clonal anergy in vitro (19). However, there is no clear evidence that this form of T cell hyporesponsiveness exists in vivo. In this study, we demonstrate that following anti-CD3 treatment, the CD28-/- T cells remaining after the initial depletion had elevated memory markers and diminished functional capacity. Thus, the classical in vitro model of costimulation-deficient anergy applies in vivo. Of the two CD28 ligands, B7-2, but not B7-1, is preferentially engaged to mediate CD28 function. This is likely due to its higher level of constitutive expression over B7-1. Many models support a requisite role of CTLA-4 in induction or maintenance of anergy in vivo (21, 23). However, anti-CD3-induced in vivo T cell hyporesponsiveness appears to be distinct in that it does not require CTLA-4 or CD28, a molecule required for maximal CTLA-4 induction.
Questions have been raised whether the lack of thymidine incorporation seen in vitro following anti-CD3 treatment is a result of hyporesponsiveness or cell death. T cells from Fas-deficient lpr mice display defects in both AICD and anergy induction, suggesting that the two processes may be linked (37, 38, 39). It has been suggested that hyporesponsiveness merely reflects an increased propensity of activated T cells to undergo cell death in vitro. In this report, we show that CD28-/- Bcl-xL-transgenic T cells are protected from anti-CD3-induced cell death but are more susceptible to anergy induction. This result demonstrates that AICD and hyporesponsiveness are distinct cellular processes that can be disassociated.
It has been shown previously that signaling through CD28 and CTLA-4 controls two distinct forms of anergy in vitro (40). Results from this current study suggest that two forms of anergy can be also induced in vivo depending on whether the cells engage CD28 or not. When T cells encounter Ag without CD28 costimulation, a majority of the cells die after a few rounds of cycling due to insufficient up-regulation of Bcl-xL. The few cells that survive are rendered anergic through up-regulation of cell cycle inhibitors (41). If CD28 is engaged during TCR stimulation, CTLA-4 expression is induced. Ligation of CTLA-4 arrests cells from further proliferation. One common feature of both forms of anergy is up-regulation of cell cycle inhibitors, which have been shown to play a role in suppressing IL-2 promoter activation in addition to inhibiting cell cycle progression (41).
The selective block of T cell apoptosis, but not unresponsiveness, in the Bcl-xL transgene allowed for an exploration of the relative contribution of T cell anergy and death to anti-CD3-induced immunosuppression in vivo. In the Bcl-xL-transgenic animal, even though hyporesponsiveness was induced, anti-CD3-mediated prolongation of cardiac allograft survival was barely significant and long-lived graft survival never occurred. Thus, although T cell unresponsiveness contributes to anti-CD3 mAb-dependent immunosuppression in vivo, T cell deletion mediated by the anti-CD3 therapy appears to play a dominant role in tolerance induction in this setting. Rejection of cardiac allografts is thought to depend upon CD4+ cell function (32). In earlier studies of anti-CD3-mediated unresponsiveness, CD8+ cells remained hyporesponsive far longer than CD4+ cells (56 days vs 24 days, respectively) (4). Therefore, in a CD4+ cell-dependent transplant model, T cell depletion may play a relatively more important role than the induction of unresponsiveness by anti-CD3 mAbs. It has been reported previously that tolerance to allogeneic grafts induced by either costimulation blockade alone (42) or in combination with rapamycin (43) is dependent on apoptosis of alloreactive cells. Our results extend these previous findings to show that in vivo tolerance induced by anti-CD3 mAbs depends on T cell depletion despite their efficient induction of hyporesponsiveness. It is important to note that the new generation of FcR-nonbinding anti-CD3 mAbs that are now in clinical development have shown great promise in inducing tolerance in transplantation (44) and autoimmune settings (45) with low toxicity. Both clinically and experimentally in murine models, FcR nonbinding anti-CD3 mAbs induce less pronounced T cell depletion than their conventional counterparts. Therefore, in that setting, T cell hyporesponsiveness may become a more important immunosuppressive mechanism. We are currently conducting experiments to determine relative contributions of various mechanisms in FcR-nonbinding anti-CD3-induced immunosuppression in vivo.
Together, our results suggest that anti-CD3 treatment modulates T cell function through induction of cell death and anergy. The efficacy of anti-CD3 therapy depends on a variety of factors including relative amount of CD28 ligation, Bcl-xL up-regulation, and T cell death. These observations will help in the design of combination treatment, which includes both costimulatory blockade and anti-CD3 to achieve better immunosuppression and tolerance induction. Finally, elucidation of these regulatory pathways may suggest future directions for immune modulation.
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Footnotes |
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2 Q.T. and J.A.S. contributed equally to this work and should be considered as co-first authors.
3 Address correspondence and reprint requests to Dr. Jeffrey A. Bluestone, Diabetes Center, University of California, San Francisco, Box 0540, 513 Parnassus Avenue, San Francisco, CA 94143-0540. E-mail address: jbluest{at}diabetes.ucsf.edu
4 Abbreviations used in this paper: AICD, activation-induced cell death; ROS, reactive oxygen species; SICD, stress-induced cell death.
Received for publication September 27, 2002. Accepted for publication November 26, 2002.
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1 transgenic mice. Res. Immunol. 146:176.[Medline]
1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 68:608.[Medline]
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