SCIENCE WATCH J Am Soc Nephrol 13: 559–575, 2002

The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation

AKIRA YAMADA, ALAN D. SALAMA, and MOHAMED H. SAYEGH Laboratory of Immunogenetics and Transplantation, Renal Division, Brigham and Women’s Hospital; Division of Nephrology, Children’s Hospital; Harvard Medical School, Boston, Massachusetts.

The CD28-B7 and CD154-CD40 pathways have been de- yet complex interactions between these novel T cell costimu- scribed as the critical costimulatory pathways for T cell acti- latory pathways and both the CD28-B7 and CD154-CD40 vation. Blockade of these pathways has been reported to reg- pathways, which determine the outcome of a particular im- ulate both autoimmune and alloimmune responses in mune response in vivo. In this review, we summarize the experimental models and in human disease. However, studies biology of these pathways, highlight their roles, their hierarchy have indicated that inhibition of these pathways is insufficient of dominance and interactions, and finally promote ideas re- to reproducibly induce long-lasting immunologic tolerance in garding their therapeutic manipulation for the treatment of experimental autoimmunity and transplantation models. This autoimmune diseases and as immunotherapy in transplantation. suggests that host immune reactivity toward the autoantigens or graft may persist despite optimal blockade of these path- T Cell Activation ways. These findings may be explained by the presence of T cells require two collaborative but distinct signals for full immune mechanisms that are known to be relatively resistant activation (1,2) (Figure 1). The first signal (signal one) is to CD28-B7 and/or CD154-CD40 blockade, such as those provided by the engagement of the T cell receptor (TCR) with ϩ involving CD8 T cells (in some transplant models), primed or its specific peptide antigen, bound to the MHC molecules on memory T cells, and natural killer (NK) cells (in autoimmunity the surface of antigen-presenting cells (APC). The second and transplantation). Alternatively, other costimulatory path- costimulatory signal (signal two) is provided by engagement of ways may provide the necessary second signals for complete T T cell surface receptors with their specific ligands on APC cell activation. These two possibilities are of course not mu- (Figure 1). Signaling through the TCR alone without signal tually exclusive. The recent discovery of new members of the two can lead to a state of T cell unresponsiveness that is termed CD28-B7 family, inducible costimulator (ICOS), its ligand, anergy or to apoptosis. Importantly, not all costimulatory mol- B7RP-1, as well as programmed death–1 (PD-1) and its li- ecules provide a “positive” signal; some provide “negative” gands, PD-L1 and PD-L2, have therefore been of major inter- signals that result in physiologic termination of immune re- est. Furthermore, recent data have demonstrated that other sponses (3) (Figure 1). The balance between positive and molecules belonging to the tumor necrosis factor (TNF) super- negative T cell costimulatory signals plays a critical role in family and their receptors (TNF-R), including 4–1BB, CD30, protecting the organism against invading foreign antigens and CD134 (OX40), and CD27, and their respective ligands, preventing the development of autoimmunity. 4–1BBL, CD30L, CD134L, and CD70, also act as efficient costimulatory molecules for T cells. The important role that The Conventional T Cell Costimulatory these newly discovered pathways play in regulation of T cell Pathways responses in both autoimmunity and transplantation is only The CD28/CTLA4-B7 Pathway now becoming apparent. In some cases, these pathways may be The CD28-B7 T cell costimulatory pathway is one of the subdominant (or redundant) and exert potent effects on T cell best characterized and is critical for T cell activation (4–7) reactivity only in the absence of or after suboptimal costimu- (Figure 2). CD28, present on T cells, has two known ligands, lation through CD28-B7 and CD154-CD40. However, in other B7–1 (CD80) and B7–2 (CD86), both of which are expressed cases these pathways can play a pivotal role in T cell activation primarily on activated APC, such as dendritic cells, macro- or differentiation that may be dependent on the particular stage phages, and B cells. When activated, T cells upregulate of the ongoing immune response. Finally, there are important CTLA-4, a molecule that is structurally similar to CD28 that also binds both B7–1 and B7–2. Interaction of CD28 with B7–1 and B7–2 provides a positive signal, which results in full Correspondence to Dr. Mohamed H. Sayegh, Laboratory of Immunogenetics T cell activation, including cytokine production, clonal expan- and Transplantation, Renal Division, Department of Medicine, Brigham and sion, enhanced T cell survival, and provision of B cell help (8). Women’s Hospital and Harvard Medical School, Boston, MA 02115. Phone: 617-732-5259; Fax: 617-732-5254; E-mail: [email protected] CTLA-4 has a higher affinity for B7–1 than B7–2, and func- 1046-6673/1302-0559 tions to provide a “negative” signal resulting in physiologic Journal of the American Society of Nephrology termination of T cell responses (9–11) (Figure 1). The impor- Copyright © 2002 by the American Society of Nephrology tance of CTLA-4 as a negative regulatory costimulatory mol- 560 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 559–575, 2002

Figure 1. (A) Postive signaling pathways. T cell activation requires two signals. Signal one, the ligation of the T cell receptor with its antigen, which is presented on the surface of MHC molecules on antigen-presenting cells (APC), and signal two, the ligation of costimulatory molecules on T cells with their respective ligands on APC. Through a series of secondary signals, the T cell subsequently undergoes proliferation, cytokine production, and further differentiation into its effector state. (B) Negative signaling pathways. Some costimulatory signals can also lead to negative T cell signaling, resulting in cellular anergy, loss of proliferative capacity, and reduction of cytokine production. These pathways may also be involved in the generation of regulatory cells.

ecule for T cells is highlighted by the observation that CTLA- donor-specific tolerance in several animal models, although 4–deficient mice develop a fatal lymphoproliferative disorder this is not a universal finding in all models or strain combina- with multiorgan autoimmune disease (12,13). Furthermore, tions. In addition, CD28-B7 blockade prevents development recent evidence suggests that the CTLA-4 negative signaling (23–25) and interrupts progression (26,27) of chronic allograft pathway may be required for induction of acquired tolerance in rejection in minor antigen-mismatched transplant models. vivo (14–16). Indeed, it has been hypothesized that CTLA-4 However, B7 blockade is less effective in preventing chronic may function as a master switch for peripheral T cell tolerance vasculopathy in fully allogeneic transplant models, in which (17). Therefore, strategies that promote CTLA4-mediated neg- chronic administration of CTLA4Ig or co-administration of ative signaling could be very useful therapeutically in T cell– donor antigen with CTLA4Ig is required to attenuate develop- mediated diseases. Ligation of CD28 by B7–1orB7–2 can be ment of chronic rejection (28,29). Interestingly, while blockade blocked by anti-B7–1 or anti-B7–2 monoclonal antibodies, of both B7–1 and B7–2 are necessary to prevent allograft respectively, or by CTLA4Ig, a recombinant fusion protein rejection and promote long-term engraftment in acute rejection containing the extracellular domain of CTLA-4 fused to an Ig models (30), selective inhibition of signaling through B7–1is heavy chain tail. CTLA4Ig binds to both B7–1 and B7–2 with sufficient for prevention of chronic rejection (27). We have higher affinity than does CD28, and thus acts as a competitive recently reported this in a rat cardiac transplant model, where inhibitor of CD28 binding to B7–1/B7–2, resulting in blockade selective B7–1 blockade was ineffective in preventing acute of CD28-B7 costimulation. graft loss but prevented progression of chronic allograft vas- Blockade of the B7 Pathway in Transplantation. We culopathy (27). These data are consistent with those of Fu- and others (18–22) have shown that CD28-B7 T cell costimu- rukawa et al. (31), which demonstrate that allograft vasculopa- latory blockade prevents acute allograft rejection and induces thy is significantly attenuated in B7–1 knockout and B7–1/ J Am Soc Nephrol 13: 559–575, 2002 T Cell Costimulatory Pathways in Autoimmunity and Transplantation 561

Figure 2. The CD28-B7 family of costimulatory molecules. Both CD28 and CTLA4 contain a motif (MYPPPY) that is necessary for binding to B7–1 and B7–2. Other members of the family lack this motif and are therefore prevented from binding these ligands. The net effect on cellular function after stimulation through these pathways is dependent on the temporal expression patterns of these molecules during T cell activation and the combination of positive and negative signals delivered.

B7–2 double knockout but not B7–2 knockout mice compared Blockade of B7 Pathway in Autoimmunity. Inhibition of with wild type littermates. the CD28-B7 pathway has also been shown to be effective in Creation of CD28 and B7–1/B7–2 deficient animals has the prevention and treatment of established diverse autoim- helped shed light into the functions of the CD28-B7 T cell mune diseases in both experimental animal models and pa- costimulatory pathways in allograft rejection. It is interesting tients. In experimental autoimmune glomerulonephritis (EAG), that although B7–1/B7–2–double deficient recipients fail to an animal model of human anti-glomerular basement mem- reject vascularized allografts (32,33), CD28-deficient animals brane (GBM) disease, there was significant attenuation of have been reported to reject allografts with some delay (34,35). clinical disease, anti-GBM autoantibody production, and renal It appears that both CD8ϩ T cells (35) and NK cells (36) play mononuclear cell infiltration in animals treated with CTLA4Ig important roles in CD28-independent allograft rejection. This (38). Furthermore, selective blockade of B7–1 by a mutant is a clinically relevant observation, because it may explain the form of CTLA4Ig produced similar disease regulation, dem- mechanisms of resistance to CD28-B7 blockade in some allo- onstrating that B7–1–mediated signaling is central to autore- graft models (37). Whether these CD8ϩ T cells are dependent active T cell activation in this model. Differential effects of on one or more of the new T cell costimulatory pathways for signaling by B7–1orB7–2 have also been demonstrated in activation remains to be determined (see below). other autoimmune models, including lupus nephritis in the 562 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 559–575, 2002

MRL-lpr/lpr mice, experimental autoimmune encephalomyeli- questioned, however, whether CD154 acts directly to transduce tis (EAE), and diabetes in susceptible nonobese diabetic a costimulatory signal to the T cell, or indirectly, as ligation of (NOD) mice. Combined blockade of B7–1 and B7–2inMRL CD40 on APC is a strong inducer of B7 expression (55,56). mice attenuated lupus-like renal disease and was associated CD154-CD40 Blockade in Transplantation. Larsen et with suppressed autoantibody production. However, deficiency al. (57) have shown that blocking this pathway with an anti- or inhibition of B7–1orB7–2 alone resulted in similar levels body to CD154 is efficient in preventing acute graft rejection of pathogenic autoantibodies. Only in the animals lacking in a mouse cardiac allograft model. Our group (58) reported B7–2 was there diminished renal Ig deposition and attenuated similar results and demonstrated downregulation of B7–1 ex- pathology (39). The B7–1–deficient animals developed more pression in cardiac allografts of animals treated with anti- severe nephritis despite similar autoantibody levels, further CD154. In our study (58) and in a study by Parker et al. (59) demonstrating the lack of correlation between antibody titer using islet transplantation, coadministration of donor cells syn- and disease (40). In EAE, treatment of animals with anti-B7–1 ergizes with CD154 blockade to prolong graft survival and antibody prevents the development of disease, whereas anti- induce donor-specific tolerance. In addition, this strategy re- B7–2 antibody exacerbates it (41), although this is not a sulted in the prevention of chronic rejection (60), although universal observation in all models (42,43). In the NOD mice, others have found contradictory data. CD154 blockade alone anti-B7–2 treatment suppresses diabetes, but anti-B7–1 anti- was found not to prevent the development of chronic rejection body alone or in combination with anti-B7–2 antibody accel- (61,62), and Shimizu et al. (63) recently showed that CD154- erates disease. Furthermore, only early treatment with anti- deficient animals develop chronic allograft vasculopathy de- B7–2 prevents the development of diabetes, but it interestingly spite long-term allograft survival. In these cases, it has been has no effect on the inflammatory insulitis (44). B7 costimu- suggested that CD154 blockade–resistant CD8ϩ T cells (61), lation signaling through CD28 is also implicated in the devel- perhaps through one or more of the new pathways, may play a opment of collagen-induced arthritis, autoimmune thyroiditis, role in the pathogenesis of chronic allograft rejection. autoimmune uveitis, and myasthenia gravis (39,40,45–48). A number of studies have demonstrated synergy between B7 However, CD28-B7 blockade may not completely abrogate and CD154 blockade with or without donor antigen. Larsen et disease, but rather diminishes severity and alters T cell and al. (62) reported that simultaneous inhibition of these two antibody phenotypes. In experimental myasthenia, for exam- pathways led to prolongation of murine skin allograft survival ple, CD28 deficiency renders animals less susceptible to dis- and prevented the development of chronic cardiac allograft ease, but only deficiency of CD154 (see below) confers com- vasculopathy. Wekerle et al. (64,65) reported that combined plete disease resistance (45). Furthermore, although CD28 B7 and CD154 blockade may substitute for T cell depletion deficiency protects animals from EAE, disease can be induced and irradiation (when high-dose donor bone marrow was used), after second immunization with antigen, suggesting that alter- in the induction of mixed allogeneic chimerism and deletional native pathways can be used for full T cell activation (49). tolerance in a mouse skin transplant model. Similar observa- B7 blockade by CTLA4Ig has been studied in patients in a tions were reported by Larsen’s group (66), which used CD154 phase I trial as treatment for severe psoriasis vulgaris (50,51) blockade and donor bone marrow. and in phase II trials for therapy of rheumatoid arthritis. Preclinical studies indicating the efficacy of CTLA4Ig and a CTLA4Ig is currently undergoing trials in other patient groups, humanized anti-CD154 monoclonal antibody in primate renal including those with multiple sclerosis and lupus nephritis and (67,68) and islet (69–71) transplantation models have also in renal transplant recipients (8,52). There are currently more been reported. Both these agents have been shown to prolong preparations of CTLA4Ig that are being tested clinically. In graft survival, but there are no data to indicate that by them- addition, there are several preparations of humanized anti- selves they reproducibly induce donor-specific tolerance in B7–1 and anti-B7–2 monoclonal antibodies. Importantly, the primates (72). However, when anti-CD154 monoclonal anti- experimental animal data showing distinct functions of B7–1 body was used as part of a strategy to induce mixed allogeneic and B7–2 in regulating the autoimmune response in various chimerism in a renal transplant model (73), the primates did disease models underscores the need to design tailor-made develop donor-specific tolerance. However, some recipients therapeutic strategies in humans with various autoimmune developed thromboembolic complications that responded to diseases. anticoagulation with heparin. Such a complication was also observed in some humans entered in the phase I-II renal The CD154-CD40 Pathway transplant trial with the humanized anti-CD154 (Biogen Inc., There has recently been much interest in studying the role of Cambridge, MA) monoclonal antibody, resulting in premature CD154 and its ligand CD40 in the process of allograft rejection termination of the trial. The exact mechanisms underlying and in the regulation of autoimmune disease (8,53). CD154 is these complications and the plans for future development of expressed on activated T cells, and CD40 is expressed on APC, this agent in transplantation remain unclear. including B lymphocytes. CD154-CD40 interaction provides a Of interest is the interaction between conventional immuno- bidirectional signal for T and B cell activation, thus underlying suppressive drugs and costimulatory pathway blockade. Al- its importance in T cell–B cell collaboration. CD40 signaling though some drug regimens (containing calcineurin inhibitors) of B cells is critical for Ig switching, and the absence of CD154 may be detrimental to the effects of T cell costimulatory characterizes the hyper IgM X-lined syndrome (54). It has been blockade (57,68,74), others (such as rapamycin) may be ben- J Am Soc Nephrol 13: 559Ð575, 2002 T Cell Costimulatory Pathways in Autoimmunity and Transplantation 563 eficial (75). The working hypothesis is that calcineurin inhib- The Novel Costimulatory Pathways itors may inhibit, while rapamycin promotes, activation-in- Several novel T cell costimulatory pathways have recently duced T cell death (AICD), a mechanism that is required for been described (85). The ICOS–B7RP-1 and PD-1–PD-L path- induction of tolerance by CD154 and B7 blockade (75,76). ways are related to the CD28-B7 family (Figure 2). Further- Calcineurin inhibitors also inhibit expression of CTLA4 (77), more, several new members of the TNF–TNF-R superfamily, which may be necessary for induction of tolerance by T cell of which CD514-CD40 is the prototype, have also been found costimulatory blockade (30). However, we have recently to be efficient costimualtory molecules (Figure 3). The expres- shown that while rapamycin is indeed synergistic with CD154 sion patterns and functions of these pathways are complex and blockade, calcineurin inhibitors do not universally impair long- as yet not clearly defined in experimental systems including term graft survival in all models (78,79). In our model, late autoimmunity and transplantation. Few data are available re- introduction of calcineurin inhibitors to animals treated with garding the in vivo expression of the molecules involved and CD154 blockade, led to the development of chronic allograft their roles in human disease. In addition, their potential inter- vasculopathy, indicating that this type of strategy may not be actions with the CD28/CTLA4-B7 and CD154-CD40 path- clinically desirable in humans (78). These collective observa- ways remain incompletely understood. Their roles are being tions demonstrate that the interactions between T cell costimu- investigated by using a combination of monoclonal antibodies, latory blockade and immunosuppressive drugs are complex but fusion proteins, and novel gene knockout animals. We have extremely important to understand so as to develop clinically begun to understand how these molecules are regulated during relevant strategies to translate into humans. immune responses and what effects they exert. Finally, data are CD154-CD40 in Autoimmunity. In numerous autoim- emerging on the interactions between these novel pathways mune diseases, blockade of the CD154-CD40 pathway has and conventional immunosuppressive agents, which will be been shown to abrogate or suppress disease. This is especially important in the planning of future treatment strategies in both true of diseases in which B cell activation is of fundamental transplantation and autoimmunity. importance, such as systemic lupus erythematosus (SLE) and myasthenia gravis (MG), because the CD154-CD40 pathway is critical in T cell–B cell interaction and activation. For example, Novel CD28/CTLA4-B7 Family Pathways (Figure 2) in models of SLE, disease may be retarded by a brief treatment The ICOS–B7RP-1 Pathway. The newly discovered course with anti-CD154 antibody (80). In experimental MG, CD28 homologue, ICOS, is a T cell costimulatory molecule blockade of the CD40 pathway alone renders the animals first reported on activated human T cells (86,87). Human ICOS completely resistant to disease induction (45). Other autoim- shares 24% identity (and 39% similarity) with human CD28 mune diseases can also be modulated by blockade of this and 17% identity (and 39% similarity) with human CTLA-4 pathway. Using models of spontaneous diabetes in rodents, (88). The MYPPPY motif, which is required for the binding of recurrence of autoimmunity (in transplanted isografts) was CD28 and CTLA-4 to B7 ligands (89), is not conserved in diminished after treatment with anti-CD154 antibodies, al- ICOS; instead, it is replaced by a FDPPPF motif. Thus, ICOS though the efficacy was greater in rats than mice (81,82). This does not bind B7–1orB7–2. Similarly, the L-ICOS ligand, is consistent with previous observations indicating that CD154 B7RP-1 (which has also been named L-COS, B7h, B7H-2, blockade protected NOD mice from developing diabetes when GL-50) (87,90–93) binds ICOS but not CD28 or CTLA-4. therapy is initiated early but that therapy was ineffective for In a similar manner to CD28, signaling through ICOS can established disease (83). result in enhanced T cell proliferation and cytokine production, In EAE, deficiency of CD40 within the central nervous induce T cell upregulation of CD154, and stimulate T cells to system is sufficient to diminish the intensity and duration of provide help for Ig production by B cells (86). However, ICOS disease, despite the demonstration of adequate T cell activation has several properties that are distinct from CD28 and thus within the peripheral immune system (84). Although CD154- make it particularly intriguing. Whereas CD28 is constitutively CD40 blockade alone is highly efficacious in autoimmune expressed on T cells, ICOS is induced after TCR engagement disease, as is found in certain transplantation models, there is and is thus expressed only on activated T cells and resting synergy with blockade of the B7-CD28 pathway. For example, memory T cells (87), suggesting an important role in providing in a model of SLE, CD154-CD40 blockade alone retards costimulatory signals to activated T cells (94). This is of some disease, but when combined with CTLA4Ig therapy, renal importance because it is known that unlike antigen-inexperi- disease may be completely prevented and survival significantly enced (naõ¬ve) T cells, which require CD28 signaling for pro- improved (80). liferation and cytokine production, optimal activation and dif- Humanized anti-CD154 antibodies are currently undergoing ferentiation of recently activated T cells or memory cells can phase I-II testing in autoimmune diseases, including lupus occur independently of CD28 costimulation (85,95). Expres- nephritis, although at least one preparation (Biogen Inc.) has sion of ICOS is enhanced by CD28 costimulation, and ICOS been associated with thromboembolic complications, and those upregulation is markedly reduced in the absence of B7Ð1 and trials have been terminated prematurely (see above). Other B7Ð2, suggesting that some of the functions ascribed to CD28 preparations (IDEC Pharmaceuticals, San Diego, CA) have not may be due in part to ICOS signaling (96). B7RP-1 expression been reported to cause similar complications and are currently is still incompletely understood. Early data suggests that it may under investigation. be constitutively expressed at low levels on antigen presenting 564 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 559Ð575, 2002

Figure 3. The TNFÐTNF-R superfamily of molecules. A number of ligand receptor pairs from this superfamily can act as efficient costimulatory molecules. Through their interactions, both T and B cell activation may occur and result in a variety of cell effector functions.

cells and certain parenchymal cells (such as renal tubular lating B7RP-1 and upregulating B7Ð1/B7Ð2 (95). What role epithelial cells, prostate epithelial cells and brain tissue) and this pattern of parenchymal expression plays in regulation of appears to be upregulated in inflammatory states (97,98). immune responses in normal and diseased tissue remains to be Whereas interferon-␥ (IFN-␥) stimulation upregulates both determined. B7RP-1 and B7Ð1/B7Ð2 on dendritic cells (DC), TNF-␣ and The functional effect of ICOS ligation was demonstrated by lipopolysaccharide (LPS) have differential effects, downregu- using a signaling anti-ICOS monoclonal antibody, which re- J Am Soc Nephrol 13: 559Ð575, 2002 T Cell Costimulatory Pathways in Autoimmunity and Transplantation 565 sulted in enhanced T cell proliferation and production of sev- kaynak et al. (97) recently demonstrated that the blockade of eral cytokines (interleukin-4 [IL-4], IL-5, IL-10, IFN-␥, ICOSÐB7RP-1 pathway effectively inhibited the development TNF-␣, and GM-CSF) (86). ICOS may have a critical role in of chronic rejection in association with CD154-CD40 pathway regulating Th2 cell differentiation. The inducible expression of blockade, using a murine cardiac transplant model. Further- ICOS and its preferential induction of IL-4 and IL-10 suggest more, ICOS blockade prevented acute rejection and, with con- that ICOS may amplify and regulate T helper cell differentia- current donor-specific transfusion or cyclosporine, induced tion. Coyle et al. (94) have reported that ICOS is an important long-term graft survival. costimulatory receptor for both recently activated T cells and The contribution of ICOS to T cellÐmediated immune re- for Th2 but not Th1 effector cells. Inhibition of ICOS may be sponses and the functional consequences of ICOS inhibition effective in suppressing the function of recently activated T may be critically influenced by both the nature of the immune helper cells, inhibiting the secretion of both IL-4 and IFN-␥. response and the timing of intervention with ICOS blockade However, under circumstances where strong immune deviation strategies. For example, the effect ICOS blockade had on the occurs, the contribution of ICOS to T cell activation may be development of EAE was in part dependent on the disease restricted to Th2 helper cells. Indeed, ICOS-Ig administration stage (induction or effector stage) when it was administered. suppressed Th2 cellÐmediated airway hyperreactivity in the Treatment with anti-ICOS antibody during antigen priming absence of suppressive effects on Th1-mediated alterations in (days 1 to 10) resulted in worsening of disease, increased airway functions (94). IFN-␥ production, increased chemokine expression, greater T ICOS costimulation is involved in both alloimmune re- cell proliferation, and reduced IgG1 antibody levels, all con- sponses and those to nominal antigens, because ICOSÐB7RP-1 sistent with a greater Th1 response. Delayed treatment (days 9 blockade with ICOS-Ig fusion protein suppressed proliferation to 20) produced the opposite effect, with significantly attenu- of T cell responding to allogeneic DC as well as to tetanus ated disease, decreased IFN-␥ production, and reduced chemo- toxoid in vitro (90). In vivo studies have suggested complex kine expression and cellular infiltration into the target organ interactions between ICOS and the CD28-B7 and CD154- (102). CD40 pathways. Inhibition of ICOS in CD28-deficient mice Current investigations are actively aimed at exploring the further reduced Th1/Th2 polarization in murine viral and par- functions and mechanisms of ICOSÐB7RP-1 interactions in asitic infection models (99). Blocking of ICOS alone had a various transplantation and autoimmune models. limited but significant capacity to downregulate T helper cell PD-1 and its Ligands, PD-L1 and PD-L2. The newest subset development. In contrast, cytotoxic T lymphocyte member of the CD28 superfamily to be described is PD-1. Like (CTL) responses remained unaffected by blocking ICOS. CD28, ICOS, and CTLA4, it is a transmembrane protein of the Taken together, these data suggest that ICOS can regulate both Ig superfamily, and like CTLA4 it possesses only a single CD28-dependent and CD28-independent CD4ϩ subset re- V-like domain and an immunoreceptor tyrosineÐbased inhib- sponses but not CD8-mediated CTL responses in vivo (99). itory motif (ITIM) within its cytoplasmic tail (Figure 2). It ICOS-deficient mice exhibit profound deficits in Ig isotype shares 23% homology with CTLA4, but it lacks the MYPPPY class switching and germinal center formation. Class switching motif required for B7Ð1 and B7Ð2 binding. PD-1 receptor is can be restored in ICOS-deficient mice by CD40 stimulation, found on activated T and B cells as well as myeloid cells such demonstrating critical interactions between the ICOSÐB7RP-1 as macrophages. It binds two known ligands, PD-L1 and PD- and the CD154-CD40 pathways (100). Differentiated ICOS- L2, found on professional APC, such as DC and monocytes, deficient cells are able to produce IFN-␥ and IL-10 but fail to but also found constitutively on certain parenchymal cells (in express IL-4 upon restimulation. Furthermore, significantly the heart, lung, and kidney) as well as on a subpopulation of T higher numbers of CD4ϩ ICOS-deficient T cells retain the and B cells (103,104). In an analgous manner to CTLA4, naõ¬ve phenotype (CD62Lhigh) after cellular activation. ICOS- engagement of PD-1 by its ligands results in a negative regu- deficient T cells do not proliferate in response to immunogens latory effect, with inhibition of downstream cellular signaling (such as keyhole-limpet hemocyanin) administered in alum, events, diminished cellular proliferation, and cytokine produc- but they do if the antigen is coadministered with complete tion. However, some of these effects are dependent on antigen Freund’s adjuvant (CFA), suggesting that strong inflammatory dose. For example, at high antigen concentrations, cytokine responses induced by the CFA can bypass the requirement for production but not cell proliferation is diminished (104). Fur- ICOS. ICOS is not required for Th2 differentiation, but rather thermore, PD-1 deficiency (similar to CTLA4) results in auto- regulates IL-4 and IL-13 production by effector cells. In EAE, immune phenomena, including splenomegaly, B cell expan- ICOS-deficient mice developed greatly enhanced disease com- sion with increased serum immunoglobulins, lupus-like pared with wild type mice (101). This may reflect impaired glomerulonephritis, arthritis, and autoimmune cardiomyopathy production of the regulatory Th2 cytokines IL-4, IL-13, and/or (105). The exact phenotype varies dependent on the back- IL-10. ground strain in which the knockouts are generated. PD-1 Collectively, the above data demonstrate that ICOS stimu- ligation is sufficient to downregulate suboptimal CD28-medi- lation is important in T cell activation and differentiation, and ated signaling (103). Thus, after T cell activation both CTLA4 in T cellÐB cell interactions. In addition, there are complex, yet and PD-1 are upregulated and serve to contain the T cell important, interactions between the ICOSÐB7RP-1 pathway response. Both molecules therefore appear to play important and the CD28-B7 and CD154-CD40 pathways. Indeed, Oz- roles in the maintenance of tolerance. Although PD-1 defi- 566 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 559Ð575, 2002 ciency leads to some modulation of thymic selection (106), it ing IL-2 production by resting CD4ϩ T cells, confirming that appears to play a more prominent role in peripheral rather than 4Ð1BBL can also play a role in antigen-specific CD4ϩ T cell central tolerance. The possible expression of PD-L on paren- responses (118). Moreover, antiÐ4-1BB monoclonal antibody chymal cells (which can upregulate class II MHC and present can induce helper T cell anergy and effectively block T cellÐ antigens to T cells, but do not express B7) suggests that dependent B cell responses (119). PD-1ÐPD-L signaling may to some extent underlie the tolero- After repeated stimulation, human CD4ϩ T cells proliferate genic capacity of these nonprofessional APC. By way of con- negligibly in response to anti-CD3 and anti-CD28 monoclonal trast, early reports suggest that B7RP-1 (the ICOS ligand) is antibodies (mAb) but show enhanced responses to combined upregulated on parenchymal cells, such as renal tubular epi- anti-CD3, anti-CD28, and antiÐ4-1BB mAb (120). These data thelial cells, after activation (for example, by IFN-␥ in vitro) suggests that 4Ð1BB plays a later role in the immune response (98). The net effect of signaling through these different path- than CD28 and that 4Ð1BB functions to perpetuate the immune ways on T cells present in inflamed tissues will therefore be response after CD28 downmodulation. Whereas antiÐ4-1BB complex, and the balance may dictate the final outcome of the mAb preferentially stimulate CD8ϩ T cell proliferation, CD28 immune response. ligation exerts a more significant proliferative effect on CD4ϩ cells (115,121). The 4Ð1BB may, however, be subdominant, The TNF–TNF-R Pathways (Figure 3) because response of naõ¬ve CD8ϩ T cells is dependent on The CD154-CD40 interaction is the prototypic pathway of 4Ð1BB only when CD28 molecules are absent (85). Further- the TNFÐTNF-R superfamily of molecules, representing one of more, whereas CD28 plays a role in initial T cell expansion, a series of receptor-ligand interactions that are important in T 4-1BBÐ4-1BBL exerts its effects by sustaining established cell activation and T cellÐB cell interactions. These pathways CD4ϩ and CD8ϩ T cell responses and enhancing cell division have the capacity to both provide direct T cell costimulation and T cell effector function (122). 4-1BBÐ4-1BBL interaction and interact with other costimulatory pathways such as contributes to the development of an allogeneic Th2 response CD28-B7 and ICOSÐB7RP-1. The TNFÐTNF-R superfamily by CD4ϩCD28Ϫ T cells (123). However, treatment of acti- contains a number of member pairs, including 4Ð1BB-4Ð vated human T cells with an intact CD28 pathway using 1BBL, CD30-CD30L, CD134-CD134L, and CD70-CD27. antiÐ4-1BB promotes a Th1 response (120). Therefore, the T Each of these molecular receptor-ligand interactions has been cell response and phenotype that results is dependent on not reported to have unique costimulatory functions. These will be only the ligation of 4Ð1BB but on the status of the CD28-B7 discussed individually. Although other newly described mem- pathway. Because 4Ð1BB may function during the later stages bers of the family, such as LIGHT-HVEM (107), also exist, of an immune response, possibly to sustain T cell activation there are as yet limited data on their role in autoimmunity and after CD28 downregulation, it may be of importance in con- transplantation and they will not be considered further in this ditions of chronic immune stimulation. review. Treatment with a stimulating antiÐ4-1BB monoclonal anti- The 4-1BB–4-1BBL Pathway. 4-1BB (CD137, ILA), a body leads to accelerated allograft rejection in both murine member of the TNF-R family, exists as both a 30-kD monomer heart and skin transplantation models (115). CD28 or 4-1BBLÐ and a 55-kD homodimer (108). 4Ð1BBL is a member of the deficient mice reject both MHC and minor antigen-incompat- TNF family and exists as a disulfide-linked homodimer (109). ible skin grafts without delay, and CD28/4Ð1BB double-defi- 4Ð1BB is primarily expressed on activated CD4ϩ and CD8ϩ T cient mice experience prolonged graft survival for both cells (108) as well as on activated NK cells (110). 4Ð1BB mismatches (although all of the grafts were eventually rejected expression peaks 2 to 3 d after cell activation (108,111). within 30 d) (117). Tan et al. (124) reported that both 4Ð1BB 4Ð1BBL is expressed on mature DC (112) and on activated B and 4Ð1BBL transcripts were expressed in rejecting grafts cells and macrophages (113). However, due to the initial low using a murine cardiac transplant model. They also demon- levels of expression of 4Ð1BBL after activation (85) it has strated that 4Ð1BB promotes CD8ϩ T cell proliferation by both been suggested that this pathway would not play a major role enhancing signals through the IL-2 receptor and by other in the initiation of the immune response. Furthermore, antiÐ4- IL-2Ðindependent mechanisms. 1BB monoclonal antibody has a greater effect on previously Interestingly, transfection of either B7Ð1orB7Ð2 into cer- activated T cells than on resting T cells, preventing the cells tain lymphoma cell lines does not render the lines immuno- from undergoing AICD (111). Like CD95 (Fas), another genic, but the additional transfection of 4Ð1BBL results in a TNF-R member, 4Ð1BB is involved in induction of lympho- tumor that is highly immunogenic and can confer long-lasting cyte apoptosis. Although 4Ð1BB induces expression of CD95 protection against subsequent challenge with parental tumor in on resting primary T and B cells, induction of apoptosis by vivo (125). Furthermore, the 4-1BBLÐexpressing tumors were 4Ð1BB is independent of CD95 because anti-CD95 antibody capable of priming CTL responses against 4-1BBLÐtransfected fragments do not block 4Ð1BB-induced apoptosis (114). as well as parental tumors in the absence of CD28, although Stimulation of 4Ð1BB induces higher levels of CD8ϩ than cytokine production was lower, resulting in a weaker CTL CD4ϩ T cell proliferation (115) and appears to be critical for recall response and reduced ability to survive challenge with CD8ϩ T cell survival (116). Furthermore, 4-1BBLÐdeficient parental tumor (126). mice have an impaired ability to generate CTL responses to In primary mixed lymphocyte reactions, a significant reduc- influenza virus (117). However, 4Ð1BB participates in promot- tion in the response was observed when either 4Ð1BBFc or J Am Soc Nephrol 13: 559Ð575, 2002 T Cell Costimulatory Pathways in Autoimmunity and Transplantation 567

CTLA4Ig was added to the cultures, although CTLA4Ig had antibody resulted in preferential development of antigen-spe- the greater effect (127). In other strain combinations, 4-1BBÐ cific T cell lines and clones showing a Th2-like profile of alkaline phosphatase conjugate (4-1BBÐAP) and CTLA4Ig cytokine secretion. Furthermore, blockade in bulk culture of added individually profoundly blocked proliferation of allo- CD30-CD30L interaction shifted the development of antigen- reactive T cells, and the combination of the two completely specific T cells toward Th1-like phenotype (140). These ob- abrogated the response (128). Furthermore, measurement of servations suggest that CD30 triggering of activated Th cells CTL responses demonstrated that CD28ϩ T cells killing allo- by CD30L-expressing APC may represent an important co- geneic target cells were only moderately inhibited by blocking stimulatory signaling for the development of Th2-type re- of 4-1BBÐ4-1BBL interaction, whereas CD28-deficient T cell sponses. However, contrary to the in vitro observation, in vivo killing of the allogeneic target was completely blocked by blockade of CD30L could not abrogate murine experimental inclusion of 4-1BBÐAP in the cultures (117). Thus, 4Ð1BBL leishmaniasis, a Th2-mediated disease (141). and CD28 may play redundant roles in allogeneic CTL re- CD30 signaling limits the proliferative potential of autore- sponses. The functions of the 41BB-4Ð1BBL in costimulation active CD8ϩ effector T cells and protects the body against of CD8ϩ T cells makes it an attractive target for investigation autoimmune diabetes mediated by CD8ϩ T cells in mice (142). in models where conventional T cell costimulatory blockade of Furthermore, transplantation of CD30-deficient mice, both B7 and CD154 are not optimally effective (37). MHC class I and class II disparate skin or heart grafts, were The CD30-CD30L Pathway. CD30 was originally de- rejected faster than control animals (143). This could be due to scribed as a marker of Reed-Sternberg cells in Hodgkin lym- impaired apoptosis of alloreactive T cells or due to an imbal- phoma (129). CD30 is expressed by activated but not by ance of the alloimmune response toward a Th1 phenotype. resting B or T cells (129Ð133). It has been proposed that CD30 Further studies are required to explore the effects and mecha- is preferentially expressed on Th2 cells (130), although this is nisms of CD30-CD30L blockade in experimental models of not universally accepted (134). T cell expression of CD30 is autoimmunity and transplantation. dependent on the presence of CD28 costimulatory signals or The CD134-CD134 Pathway. CD134 (OX40) was origi- exogenous IL-4 during primary T cell activation (131). CD30L nally identified as a cell surface antigen on activated rat CD4ϩ is a transmembrane protein of the TNF family that is expressed T cells. The human, rat, and mouse CD134 genes were subse- by T and B lymphocytes, macrophages, and a variety of he- quently cloned and shown to belong to the TNF-R superfamily matopoietic cells and tumors (135,136). Using activated (144Ð146). CD134 ligand (OX40L) is a type II membrane splenocytes, it was demonstrated that CD30L is expressed protein with limited homology to TNF and has been shown to primarily on CD4ϩ T cells, with peak expression at days 1 and bind to and costimulate CD134ϩ T cells in vitro (147,148). 2, whereas CD30 is expressed primarily on CD8ϩ T cells, with When CD134 is engaged by anti-CD134 monoclonal antibody peak expression on days 4 and 5 (130). The CD30L has been or CD134L it generates a costimulatory signal that can be as reported to act both as a costimulator for the proliferation of T potent as CD28 (149). Engagement promotes effector and cells and as a mediator of cytotoxicity through induction of memory-effector T cell functions by upregulating IL-2 produc- apoptosis (135,136). Mice deficient in CD30 showed a mild tion and increasing the life span of effector T cells. impairment in thymic negative selection, and activation-in- Expression of CD134 is restricted to activated T cells in duced death of thymocytes after CD3 crosslinking is impaired humans and rodents (145,150). Expression of CD134L has both in vivo and in vitro (137). been documented on activated murine B cells (145,151), hu- Although function of CD30-CD30L interaction is largely man dendritic cells (152), human vascular endothelial cells unknown, in vitro studies have shown that it has effects on both (153), and HTLV-1-transformed T cells (154). Both in vitro cell activation and cell death (130,131,133,135,138,139). and in vivo activation of naõ¬ve T cells results in transient Gruss et al. (135) demonstrated that CD30-CD30L interaction expression of CD134 with a peak at 24 to 48 h and down enhance or reduce proliferation of many different CD30ϩ regulation by 96 to 120 h (155). Although CD134 expression is human lymphoma cell lines. Using lymph node cells, Gilfillan augmented by CD28, it can occur independently (156). et al. (131) showed that CD30 signaling has a costimulatory The CD134-CD134L pathway appears to be particularly effect during a secondary stimulation with anti-CD3. In addi- important for regulating the extent of CD4ϩ T cell expansion tion to this role in cell proliferation, CD30 signaling also in the primary T cell response and thus the ability of T cells to regulates T cells by inducing apoptosis. Lee et al. (139) re- persist as a population over time (157). CD134-deficient T ported that in combination with signals transduced by the TCR, cells secrete IL-2 and proliferate normally during the initial CD30 signaling induces Fas-independent cell death in T cell period of activation, but cannot be sustained during the latter hybridomas. Moreover, Telford et al. (133) showed that CD30- phases of the primary response and exhibit decreased survival regulated, Fas-independent apoptosis occurred in murine over time. Mice lacking CD134 generate lower frequencies of CD8ϩ T cells after cessation of TCR signals. Several reports antigen-specific CD4ϩ T cells late in the primary response and have shown that CD30-CD30L interaction induces immune lower frequencies of surviving memory cells as compared to deviation to Th2. Stimulation of CD30 by plate-bound agonis- wild type animals. Furthermore, CD134 and CD134L-deficient tic anti-CD30 directly signaled for IL-5 but not IFN-␥ produc- mice demonstrate not only impaired T cell proliferation but tion by CD30ϩ CTL lines (130). In addition, costimulation of also diminished Th1 and Th2 cytokine production (155,158Ð peripheral blood mononuclear cells with agonistic anti-CD30 161). Therefore CD134-CD134L interactions help regulate pri- 568 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 559Ð575, 2002 mary T cell expansion and T cell memory (157). This function proliferation and cytokine production, especially IL-2 produc- may be particularly relevant for chronic autoimmune diseases tion (155). It is possible that while CD28-B7 costimulation and development of chronic rejection where prolonged antigen regulates early events, driving cell cycle progression and initial exposure occurs. T cell expansion, the CD134-CD134L interaction promotes a Early studies suggested that CD134-CD134L interactions more sustained cytokine and proliferative response. This would were also necessary for B cell activation and humoral immu- lead to less cell death and higher frequencies of antigen- nity (151,162). However, studies using CD134- and CD134L- specific T cells. Therefore, blockade of this pathway may deficient mice have demonstrated that CD134-CD134L inter- enhance the ability of B7 and/or CD154 blockade to promote actions are not essential (or are redundant) for germinal center deletional tolerance and may thus prove to be therapeutic formation and antibody responses to antigens or infectious importance, especially in stringent transplant models that are agents (158Ð161). However, transgenic expression of CD134 relatively resistant to B7 or CD154 blockade alone. In contrast, on dendritic cells (163) does lead to increased numbers of CD134-transgenic mice develop more severe EAE after a CXCR-5 CD4ϩ T cells in B cell follicles (156), which may delayed onset, and both CD134-transgenic/CD28-deficient and provide augmented T cell help for B cell function. Further- CD134-transgenic/CD40-deficient mice fail to develop EAE, more, CD134-deficient mice have been reported to be severely demonstrating the necessity of these molecules (171). impaired in their ability to generate a Th2 response in response The CD27-CD70 Pathway. CD27, another TNF-R super- to allergen-induced airway disease (164). These mice also family member has been implicated in T cell activation, T cell exhibit diminished lung inflammation and significantly atten- development, and T cellÐdependent antibody production by B uated airway hyperreactivity (164). CD134-CD134L is also cells (173,174). Its ligand, CD70, is a type II transmembrane important in other Th2 CD4ϩ T cell responses including in- glycoprotein belonging to the TNF family. It is found on fections with leishmaniasis (141,165). medullary thymic epithelium and is rapidly induced on both T CD134-CD134L interactions are critical in autoimmune re- and B cells after cellular activation. CD70 expression on B sponses with evidence that signaling through CD134 can break cells is enhanced by CD40 signaling and is downregulated by peripheral T cell tolerance (166). Targeting this pathway di- IL-4 (175). minishes disease in EAE (167,168) and in a model of inflam- Murine CD70 transfectants exhibit a potent costimulatory matory bowel disease (169). CD134-Ig administration to mice activity for anti-CD3Ðstimulated T cell proliferation, which is with colitis ameliorated disease was associated with reduced inhibited by anti-CD70 far more efficiently than murine tissue T cell infiltrates as well as diminished TNF-␣, IL-1, CD27-Ig (176). Using knockout animals Hendriks et al. (177) IL-12, and IFN-␥ production (169). Numerous groups have suggested that CD27 makes essential contributions to mature investigated the effect of CD134 pathway blockade in murine CD4ϩ and CD8ϩ T cell functions: CD27-supported antigen- EAE. Administration of anti-CD134L antibody effectively specific expansion (but not effector cell maturation) of naõ¬ve T ameliorated EAE in both actively induced and adoptively cells independent of the cell cycle-promoting activities of transferred models (170). Interestingly, anti-CD134L mono- CD28 and IL-2. Primary CD4ϩ and CD8ϩ T cell responses to clonal antibody treatment did not inhibit the development of influenza virus were impaired in CD27-deficient mice. Effects pathogenic T cells, their proliferative responses or IFN-␥ pro- of CD27-deficiency were most profound on T cell memory, duction as evidenced by restimulation of draining lymph node reflected by delayed response kinetics and reduction in number cells with antigen, and these cells effectively transferred EAE of CD8ϩ virus-specific T cell to levels seen in primary re- to naõ¬ve mice. However, flow cytometric analysis showed that sponses. Furthermore, in the mixed lymphocyte culture using the anti-CD134L antibody treatment inhibited the accumula- wild type mice, CD27-CD70 interaction induced the genera- tion of CD134-expressing CD4ϩ T cells in the spinal cord and tion of cytotoxic T cells (178). the migration of adoptively transferred CD4ϩ T cells. Interest- Two reports indicate that CD70 and CD134L on activated B ingly, immunohistochemical analysis revealed prominent cells could provide CD28-independent costimulatory signals to CD134L staining on endothelial cells in the inflamed spinal T cells (172,176). Moreover, CD27-CD70 interactions com- cord. What role this may play in maintenance of the immune plement CD40 ligation on B cells, playing a key role in response and cell migration remains to be defined. Recently T-dependent B cell responses, and being responsible for Chitnis et al. (49) from our group demonstrated that anti- plasma cell differentiation (179). Furthermore, CD27-mediated CD134L monoclonal antibody therapy protected animals from activation may be involved in the NK-cellÐmediated innate EAE in CD28-deficient but not wild type mice. Furthermore, immunity against virus-infected or transformed cells express- using CD134-deficient mice, Ndhlovu et al. (171) reported that ing CD70 (174). abortive T cell priming greatly reduced the clinical manifesta- Nakajima et al. (180) reported that treatment of SJL mice tions of actively induced EAE associated with a reduction in with the anti-CD70 monoclonal antibody prevented EAE. The IFN-␥, IL-2, and IL-6 production. therapeutic effect was not due to the inhibition of T cell Although there is CD28-independent costimulation of T priming and antibody production by B cells or immune devi- cells by CD134L (172), there appears to be synergy between ation, although TNF-␣ production was suppressed. Two sepa- the CD28-B7 and CD134-CD134L pathways. Studies using rate groups (181,182) recently reported that coexpression of fibroblast transfectants expressing B7Ð1 and/or CD134L dem- CD70 and B7Ð1 on tumor cells enhances antitumor immune onstrated that together CD134L and B7Ð1 enhance T cell responses, and this observation could be applicable for preven- J Am Soc Nephrol 13: 559Ð575, 2002 T Cell Costimulatory Pathways in Autoimmunity and Transplantation 569

Table 1. Potential therapeutic uses of novel T costimulatory pathways blockadea

Pathway Transplantation Autoimmunity

ICOSÐB7RP-1 Tolerance induction and prevention Abrogation of established disease, e.g., of chronic rejection MS, Graves disease, MG, psoriasis PD-1ÐPD-L Signaling molecules for induction Re-establishment of peripheral of peripheral tolerance as part of tolerance in relapsing remitting other tolerizing strategy diseases, e.g., MS, SLE, MG, ITP CD30-CD30L Role in prevention of chronic Skewing to a Th2 effector profile in rejection through Th2 switch Th1 disease and protection from CD8-mediated damage, e.g., diabetes 4-1BBÐ4-1BBL Inhibition of B7-resistant, CD8- Inhibition of effector CD8 T cellÐ mediated rejection mediated damage in autoimmunity, e.g., diabetes CD134-CD134L Induction of tolerance in Treatment of CD4-mediated disease, combination with other agents e.g., MS, RA, psoriasis CD27-CD70 Inhibition of alloantibody and Inhibition of pathogenic autoantibodies, CD8-mediated rejection e.g., Goodpasture syndrome, MG, SLE, Graves disease, pemphigus

a MS, multiple sclerosis; MG, myasthenia gravis; SLE, systemic lupus erythematosus; ITP, immune thrombocytopenic purpura; RA, rheumatoid arthritis.

tion of graft rejection. The findings that the CD27-CD70 states (especially in patients where data are lacking), at what pathway is important for CD8ϩ T cell and NK cell functions as time points, and how these pathways interact with conventional well as memory T cell generation and its interaction with immunosuppressants as well as with interruption of other co- CD154-CD40 (179) suggest a key therapeutic target for pre- stimulatory pathways. Our challenge now is to further pre- vention of alloantibody-mediated chronic allograft vasculopa- cisely define the functions of these pathways and the way they thy and perhaps induction of tolerance in stringent transplant interact during autoimmune disease and after transplantation so models. Preliminary work from our group indicates that CD27- that the full potential for therapeutic manipulation can be CD70 blockade might be particularly effective in promoting realized. long-term allograft survival in CD28-deficient animals in which both CD8ϩ T cells and NK cells play a key role (35). References Conclusions 1. Bretscher P, Cohn M: A theory of self-nonself discrimination. Recent advances in our knowledge of T cell activation have Science 169: 1042Ð1049, 1970 suggested that inhibiting T cell costimulatory pathways may be 2. Janeway CA, Jr, Bottomly K: Signals and signs for lymphocyte an effective way to promote antigen-specific tolerance of trans- responses. Cell 76: 275Ð285, 1994 plants and to prevent or treat autoimmune diseases. Blockade 3. Van Parijs L, Abbas AK: Homeostasis and self-tolerance in the immune system: Turning lymphocytes off. Science 280: 243Ð of the B7 and CD154 pathways has already shown great 248, 1998 promise in certain rodent and primate transplant models and to 4. Linsley PS, Ledbetter JA: The role of the CD28 receptor during a much more limited extent in certain human diseases. How- T cell responses to antigen. Annu Rev Immunol 11: 191Ð212, ever, blockade of these conventional T cell costimulatory path- 1993 ways may not be sufficient to induce tolerance in more strin- 5. June CH, Bluestone JA, Nadler LM, Thompson CB: The B7 and gent transplant models or to inhibit the primed or memory T CD28 receptor families. Immunol Today 15: 321Ð331, 1994 cell response in autoimmune diseases. Therefore, understand- 6. Thompson CB: Distinct roles for the costimulatory ligands B7Ð1 ing the functions and mechanisms of other T cell costimulatory and B7Ð2 in T helper cell differentiation. Cell 81: 979Ð982, 1995 pathways in various immune responses may allow for a more 7. Bluestone JA: New perspectives of CD28-B7-mediated T cell efficacious blockade of T cell responses and provide hope of costimulation. Immunity 2: 555Ð559, 1995 achieving reproducible, robust tolerance in humans (183). On 8. Sayegh MH, Turka LA: The role of T-cell costimulatory activa- tion pathways in transplant rejection. N Engl J Med 338: 1813Ð the basis of the known biology of the pathways we have 1821, 1998 highlighted and the effects seen after their inhibition, it seems 9. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, likely that one or more of them may prove to be promising Ledbetter JA: CTLA-4 is a second receptor for the B cell acti- therapeutically (Table 1), possibly with combined B7 and/or vation antigen B7. J Exp Med 174: 561Ð569, 1991 CD154 blockade. Further experimental studies will be needed 10. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman to understand which pathways are critical for particular disease GJ, Green JM, Thompson CB, Bluestone JA: CTLA-4 can func- 570 Journal of the American Society of Nephrology J Am Soc Nephrol 13: 559Ð575, 2002

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