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

The CD28-B7 and CD154-CD40 pathways have been described as the critical costimulatory pathways for T cell activation. Blockade of these pathways has been reported to regulate both autoimmune and alloimmune responses in experimental models and in human disease. However, studies have indicated that inhibition of these pathways is insufficient to reproducibly induce long-lasting immunologic tolerance in experimental autoimmunity and transplantation models. This suggests that host immune reactivity toward the autoantigens or graft may persist despite optimal blockade of these pathways. These findings may be explained by the presence of immune mechanisms that are known to be relatively resistant to CD28-B7 and/or CD154-CD40 blockade, such as those involving CD8+ T cells (in some transplant models), primed or memory T cells, and natural killer (NK) cells (in autoimmunity and transplantation). Alternatively, other costimulatory pathways may provide the necessary second signals for complete T cell activation. These two possibilities are of course not mutually exclusive. The recent discovery of new members of the CD28-B7 family, inducible costimulator (ICOS), its ligand, B7RP-1, as well as programmed death–1 (PD-1) and its ligands, PD-L1 and PD-L2, have therefore been of major interest. Furthermore, recent data have demonstrated that other molecules belonging to the tumor necrosis factor (TNF) superfamily and their receptors (TNF-R), including 4–1BB, CD30, CD134 (OX40), and CD27, and their respective ligands, 4–1BBL, CD30L, CD134L, and CD70, also act as efficient costimulatory molecules for T cells. The important role that these newly discovered pathways play in regulation of T cell responses in both autoimmunity and transplantation is only now becoming apparent. In some cases, these pathways may be subdominant (or redundant) and exert potent effects on T cell reactivity only in the absence of or after suboptimal costimulation through CD28-B7 and CD154-CD40. However, in other cases these pathways can play a pivotal role in T cell activation or differentiation that may be dependent on the particular stage of the ongoing immune response. Finally, there are important yet complex interactions between these novel T cell costimulatory pathways and both the CD28-B7 and CD154-CD40 pathways, which determine the outcome of a particular immune response in vivo. In this review, we summarize the biology of these pathways, highlight their roles, their hierarchy of dominance and interactions, and finally promote ideas regarding their therapeutic manipulation for the treatment of autoimmune diseases and as immunotherapy in transplantation. T Cell Activation T cells require two collaborative but distinct signals for full activation (1,2) (Figure 1). The first signal (signal one) is provided by the engagement of the T cell receptor (TCR) with its specific peptide antigen, bound to the MHC molecules on the surface of antigen-presenting cells (APC). The second costimulatory signal (signal two) is provided by engagement of T cell surface receptors with their specific ligands on APC (Figure 1). Signaling through the TCR alone without signal two can lead to a state of T cell unresponsiveness that is termed anergy or to apoptosis. Importantly, not all costimulatory molecules provide a “positive” signal; some provide “negative” signals that result in physiologic termination of immune responses (3) (Figure 1). The balance between positive and negative T cell costimulatory signals plays a critical role in protecting the organism against invading foreign antigens and preventing the development of autoimmunity. 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.The Conventional T Cell Costimulatory Pathways The CD28/CTLA4-B7 Pathway The CD28-B7 T cell costimulatory pathway is one of the best characterized and is critical for T cell activation (4–7) (Figure 2). CD28, present on T cells, has two known ligands, B7–1 (CD80) and B7–2 (CD86), both of which are expressed primarily on activated APC, such as dendritic cells, macrophages, and B cells. When activated, T cells upregulate 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 T cell activation, including cytokine production, clonal expansion, enhanced T cell survival, and provision of B cell help (8). CTLA-4 has a higher affinity for B7–1 than B7–2, and functions to provide a “negative” signal resulting in physiologic termination of T cell responses (9–11) (Figure 1). The importance of CTLA-4 as a negative regulatory costimulatory molecule for T cells is highlighted by the observation that CTLA-4–deficient mice develop a fatal lymphoproliferative disorder with multiorgan autoimmune disease (12,13). Furthermore, recent evidence suggests that the CTLA-4 negative signaling pathway may be required for induction of acquired tolerance in vivo (14–16). Indeed, it has been hypothesized that CTLA-4 may function as a master switch for peripheral T cell tolerance (17). Therefore, strategies that promote CTLA4-mediated negative signaling could be very useful therapeutically in T cell–mediated diseases. Ligation of CD28 by B7–1 or B7–2 can be blocked by anti-B7–1 or anti-B7–2 monoclonal antibodies, respectively, or by a the of CTLA-4 to binds to both B7–1 and B7–2 with higher affinity than CD28, and as a of CD28 to resulting in blockade of CD28-B7 Figure : The CD28-B7 of costimulatory CD28 and a that is necessary for to B7–1 and B7–2. members of the this and are therefore these The on cellular function after through these pathways is dependent on the of these molecules T cell activation and the of positive and negative signals of the Pathway in and have that CD28-B7 T cell costimulatory blockade and tolerance in this is not a in all models or In CD28-B7 blockade development and of in transplant models. However, blockade is in preventing in transplant in which of or of with is required to development of blockade of both B7–1 and B7–2 are necessary to and promote in models inhibition of signaling through B7–1 is for of have reported this in a transplant B7–1 blockade in preventing graft loss but of These data are with those of which that is in B7–1 and but not B7–2 mice with of CD28 and has into the functions of the CD28-B7 T cell costimulatory pathways in is that to have been reported to with some that both CD8+ T cells and cells play important in This is a it may the mechanisms of to CD28-B7 blockade in some models these CD8+ T cells are dependent on one or of the new T cell costimulatory pathways for activation to be Blockade of Pathway in of the CD28-B7 pathway has also been to be in the and treatment of autoimmune diseases in both experimental models and In experimental autoimmune of human there of production, and cell in with Furthermore, blockade of B7–1 by a of similar disease that signaling is to T cell activation in this effects of signaling by B7–1 or B7–2 have also been demonstrated in other autoimmune including in the experimental autoimmune and in blockade of B7–1 and B7–2 in mice disease and with production. However, or inhibition of B7–1 or B7–2 alone in similar of in the B7–2 there and The despite similar further the of between and disease In treatment of with anti-B7–1 the development of anti-B7–2 it this is not a observation in all models In the anti-B7–2 treatment but anti-B7–1 alone or in with anti-B7–2 disease. Furthermore, only treatment with anti-B7–2 the development of but it has on the costimulation signaling through CD28 is also in the development of autoimmune autoimmune and However, CD28-B7 blockade may not but and T cell and In experimental for CD28 to but only of complete disease Furthermore, CD28 disease can be after second with antigen, that pathways can be for full T cell activation blockade by has been in in a as treatment for and in for of is in other including those with and and in transplant are of that are In there are of anti-B7–1 and anti-B7–2 monoclonal Importantly, the experimental data distinct functions of B7–1 and B7–2 in the autoimmune response in disease models the to therapeutic strategies in with autoimmune diseases. The CD154-CD40 Pathway has been in the role of and its in the of and in the regulation of autoimmune disease is expressed on activated T cells, and is expressed on APC, including B CD154-CD40 provides a signal for T and B cell activation, its importance in T cell signaling of B cells is critical for and the absence of the has been to a costimulatory signal to the T or as ligation of on APC is a of CD154-CD40 Blockade in have that this pathway with to is efficient in preventing graft in a reported similar results and demonstrated of B7–1 in of with In and in a by of cells with blockade to graft and induce In this in the of have blockade alone not to the development of and that develop despite In these cases, it has been that CD8+ T cells through one or of the new pathways, may play a role in the of of studies have demonstrated between and blockade with or without reported that inhibition of these two pathways to of and the development of reported that and blockade may for T cell and in the induction of and tolerance in a transplant reported by which blockade and studies the of and a monoclonal in and transplantation models have also been these have been to graft survival, but there are data to that by reproducibly induce tolerance in However, monoclonal as of a to induce in a transplant the develop However, some that to with a also in some in the transplant with the monoclonal resulting in termination of the The mechanisms these and the for development of this in transplantation is the between and costimulatory pathway some may be to the effects of T cell costimulatory blockade as may be The is that may T cell a that is required for induction of tolerance by and blockade also of which may be necessary for induction of tolerance by T cell costimulatory blockade However, we have that is with blockade, not graft in all models In of to with blockade, to the development of that this of may not be in These that the interactions between T cell costimulatory blockade and are complex but important to as to develop strategies to into CD154-CD40 in In autoimmune blockade of the CD154-CD40 pathway has been to or disease. This is of diseases in which B cell activation is of such as and the CD154-CD40 pathway is critical in T cell and activation. in models of disease may be by a treatment course with In experimental blockade of the pathway alone the resistant to disease induction autoimmune diseases can also be by blockade of this models of in of autoimmunity (in after treatment with antibodies, the in than mice This is with that blockade mice is but that for disease In of the is to the and of despite the of T cell activation the peripheral immune CD154-CD40 blockade alone is in autoimmune as is in transplantation there is with blockade of the in a of CD154-CD40 blockade alone but with disease may be and are in autoimmune including one has been with and those have been have not been reported to similar and are The Costimulatory Pathways novel T cell costimulatory pathways have been described The and pathways are to the CD28-B7 (Figure 2). Furthermore, new members of the of which is the have also been to be efficient molecules (Figure The and functions of these pathways are complex and as yet not in experimental including autoimmunity and transplantation. data are regarding the in vivo of the molecules involved and their in human disease. In their interactions with the CD28/CTLA4-B7 and CD154-CD40 pathways are by a of monoclonal antibodies, and novel have to these molecules are immune responses and effects Finally, data are on the interactions between these novel pathways and which be important in the of treatment strategies in both transplantation and autoimmunity. Figure : The superfamily of of receptor this superfamily can act as efficient costimulatory Through their interactions, both T and B cell activation may and result in a of cell effector CD28/CTLA4-B7 Pathways (Figure The The newly discovered CD28 is a T cell costimulatory molecule first reported on activated human T cells with human CD28 and with human CTLA-4 The which is required for the of CD28 and CTLA-4 to ligands is not in it is by a not B7–1 or B7–2. the ligand, has also been binds but not CD28 or In a similar to CD28, signaling through can result in enhanced T cell and cytokine production, induce T cell of and T cells to provide help for by B cells However, has that are distinct CD28 and it CD28 is expressed on T cells, is after TCR engagement and is expressed only on activated T cells and memory T cells important role in costimulatory signals to activated T cells This is of some importance it is known that T cells, which require CD28 signaling for and cytokine production, optimal activation and differentiation of activated T cells or memory cells can of CD28 costimulation of is enhanced by CD28 and is in the absence of B7–1 and B7–2, that some of the functions to CD28 may be in to signaling is data suggests that it may be expressed on cells and cells as cells, cells and and to be in both and on dendritic cells and have and role this of plays in regulation of immune responses in and to be The of ligation demonstrated by a signaling monoclonal which in enhanced T cell and of and may have a critical role in cell The inducible of and its induction of and that may and regulate T cell have reported that is important costimulatory receptor for both activated T cells and for but not effector cells. of may be in the function of activated T cells, the of both and However, immune the of to T cell activation may be to cells. Indeed, cell–mediated in the absence of effects on in functions costimulation is involved in both alloimmune responses and those to blockade with of T cell to as well as to in In vivo studies have complex interactions between and the CD28-B7 and CD154-CD40 pathways. of in mice further in and models of alone a but to T cell In T responses by these data that can regulate both and responses but not responses in vivo mice in and can be in mice by critical interactions between the and the CD154-CD40 pathways cells are to and but to Furthermore, higher of T cells the after cellular activation. T cells not in response to as in but the is with complete that responses by the can the for is not required for but and by effector cells. In mice enhanced disease with mice This may of the regulatory and/or the data that is important in T cell activation and and in T cell In there are yet interactions between the pathway and the CD28-B7 and CD154-CD40 pathways. Indeed, demonstrated that the blockade of pathway the development of in with CD154-CD40 pathway blockade, a transplant Furthermore, blockade with or graft The of to T cell–mediated immune responses and the of inhibition may be by both the of the immune response and the of with blockade the blockade on the development of in dependent on the disease stage or effector it with to in of production, T cell proliferation, and all with a response. treatment to the with production, and and cellular into the are the functions and mechanisms of interactions in transplantation and autoimmune models. and its PD-L1 and The of the CD28 superfamily to be described is CD28, and it is a of the and it only a and its (Figure 2). with but it the required for B7–1 and B7–2 receptor is on activated T and B cells as well as cells such as binds two known ligands, PD-L1 and PD-L2, on APC, such as and but also on cells (in the and as well as on a of T and B cells In to engagement of by its ligands results in a negative regulatory with inhibition of cellular signaling cellular proliferation, and cytokine production. However, some of these effects are dependent on cytokine but not cell is Furthermore, to results in autoimmune including B cell with and autoimmune The dependent on the in which the are ligation is to suboptimal signaling after T cell activation both and are and to the T cell response. molecules therefore to play important in the of to some of it to play a role in peripheral than The of on cells can upregulate MHC and present antigens to T cells, but not suggests that signaling may to some the of these APC. of that is on cells, such as cells, after activation by in The of signaling through these pathways on T cells present in therefore be and the balance may the outcome of the immune response. The Pathways (Figure The CD154-CD40 is the pathway of the superfamily of one of a series of interactions that are important in T cell activation and T cell These pathways have the to both provide T cell costimulation and with other costimulatory pathways such as CD28-B7 and The superfamily a of including and of these interactions has been reported to have costimulatory These be other newly described members of the family, such as also there are as yet data on their role in autoimmunity and transplantation and not be further in this The a of the family, as both a and a is a of the and as a is primarily expressed on activated and CD8+ T cells as well as on activated cells to after cell activation is expressed on and on activated B cells and However, to the of of after activation it has been that this pathway not play a major role in the of the immune response. Furthermore, monoclonal has a on activated T cells than on T cells, preventing the cells is involved in induction of apoptosis. of on T and B cells, induction of by is of not of higher of CD8+ than T cell and to be critical for CD8+ T cell Furthermore, mice have to responses to However, in by T cells, that can also play a role in T cell responses monoclonal can induce T cell anergy and T B cell responses human T cells in response to and monoclonal but enhanced responses to and These data suggests that plays a role in the immune response than CD28 and that functions to the immune response after CD28 CD8+ T cell proliferation, CD28 ligation a proliferative on cells The be response of CD8+ T cells is dependent on only CD28 molecules are Furthermore, CD28 plays a role in T cell expansion, its effects by and CD8+ T cell responses and cell and T cell effector function to the development of response by T cells However, treatment of activated human T cells with CD28 pathway a response Therefore, the T cell response and that results is dependent on not only the ligation of but on the of the CD28-B7 may function the of immune to T cell activation after CD28 it may be of importance in of immune with a monoclonal to in both and transplantation models CD28 or mice both MHC and without and mice graft for both all of the reported that both and expressed in a transplant also demonstrated that CD8+ T cell by both signals through the receptor and by other of B7–1 or B7–2 into cell not the but the of results in a tumor that is and can long-lasting against with tumor in vivo Furthermore, the of responses against as well as in the absence of CD28, cytokine resulting in a response and to with tumor In a reduction in the response or to the the In other and blocked of T cells, and the of the two the response Furthermore, of responses demonstrated that T cells cells only by of T cell of the blocked by of in the and CD28 may play in The functions of the in costimulation of CD8+ T cells it for in models T cell costimulatory blockade of and are not The described as a of cells in is expressed by activated but not by B or T cells has been that is expressed on cells this is not T cell of is dependent on the presence of CD28 costimulatory signals or T cell activation is a of the that is expressed by T and B macrophages, and a of cells and activated it demonstrated that is expressed primarily on T cells, with and is expressed primarily on CD8+ T cells, with on and The has been reported to act both as a costimulator for the of T cells and as a of through induction of in a in negative and of after is both in vivo and in function of is in studies have that it has effects on both cell activation and cell demonstrated that or of human cell cells, that signaling has a costimulatory a secondary with In to this role in cell proliferation, signaling also T cells by apoptosis. reported that in with signals by the signaling cell in T cell that in CD8+ T cells after of TCR signals. have that immune to of by for but not by In costimulation of peripheral cells with in development of T cell and a of cytokine Furthermore, blockade in of the development of T cells toward These that of activated cells by APC may important costimulatory signaling for the development of However, to the in in vivo blockade of could not experimental a disease signaling the proliferative of CD8+ effector T cells and the against autoimmune by CD8+ T cells in mice Furthermore, transplantation of both MHC and or than This could be to of T cells or to of the alloimmune response toward a studies are required to the effects and mechanisms of blockade in experimental models of autoimmunity and transplantation. The CD134 as a cell surface on activated T cells. The and CD134 subsequently and to to the superfamily CD134 is a with to and has been to to and T cells in When CD134 is by monoclonal or it a costimulatory signal that can be as potent as CD28 effector and T cell functions by and the of effector T cells. of CD134 is to activated T cells in and of has been on activated B cells human dendritic cells human cells and T cells in and in vivo activation of T cells results in of CD134 with a to and regulation by to CD134 is by CD28, it can The pathway to be important for the of T cell in the T cell response and the of T cells to persist as a T cells and the of activation, but be the of the response and CD134 of T cells in the response and of memory cells as to Furthermore, CD134 and mice not only T cell but also and cytokine interactions help regulate T cell and T cell memory This function may be for autoimmune diseases and development of studies that interactions also necessary for B cell activation and However, studies and mice have demonstrated that interactions are not (or are redundant) for and responses to antigens or However, of CD134 on dendritic cells lead to of T cells in B cell which may provide T cell help for B cell Furthermore, mice have been reported to be in their to a response in response to disease These mice also and is also important in other T cell responses including with interactions are critical in autoimmune responses with evidence that signaling through CD134 can peripheral T cell tolerance this pathway disease in and in a of disease to mice with disease with T cell as well as and have the of CD134 pathway blockade in of in both and models monoclonal treatment not the development of T cells, their proliferative responses or as by of cells with antigen, and these cells to However, that the treatment the of T cells in the and the of T cells. on cells in the role this may play in of the immune response and cell to be demonstrated that monoclonal in but not Furthermore, reported that T cell the of with a reduction in and production. there is costimulation of T cells by there to be between the CD28-B7 and pathways. B7–1 and/or demonstrated that and B7–1 T cell and cytokine production, is that CD28-B7 costimulation cell and T cell expansion, the a cytokine and proliferative response. This lead to cell and higher of T cells. Therefore, blockade of this pathway may the of and/or blockade to promote tolerance and may to be therapeutic in transplant models that are relatively resistant to or blockade In mice develop after a and both and mice to develop the of these molecules The CD27, superfamily has been in T cell activation, T cell and T by B cells ligand, CD70, is a belonging to the is on and is on both T and B cells after cellular activation. on B cells is enhanced by signaling and is by a potent costimulatory for T cell proliferation, which is by than that to and CD8+ T cell not effector cell of T cells of the cell of CD28 and and CD8+ T cell responses to in of on T cell by response and reduction in of CD8+ T cell to in Furthermore, in the the generation of T cells that and on activated B cells could provide costimulatory signals to T cells interactions ligation on B cells, a role in B cell and for cell differentiation Furthermore, activation may be involved in the against or cells reported that treatment of mice with the monoclonal The therapeutic not to the inhibition of T cell and by B cells or immune reported that of and B7–1 on tumor cells immune and this observation could be for of graft The findings that the pathway is important for CD8+ T cell and cell functions as well as memory T cell generation and its with CD154-CD40 a therapeutic for of and induction of tolerance in transplant models. that blockade be in in in which both CD8+ T cells and cells play a role in of T cell activation have that T cell costimulatory pathways may be to promote tolerance of and to or autoimmune diseases. Blockade of the and pathways has in and transplant models and to a in human diseases. However, blockade of these T cell costimulatory pathways may not be to induce tolerance in transplant models or to the primed or memory T cell response in autoimmune diseases. Therefore, the functions and mechanisms of other T cell costimulatory pathways in immune responses may for a blockade of T cell responses and provide of tolerance in the of the known biology of the pathways we have highlighted and the effects after their it that one or of may to be therapeutically with and/or experimental studies be to which pathways are critical for particular disease in data are and these pathways with as well as with of other costimulatory pathways. now is to further the functions of these pathways and the autoimmune disease and after transplantation that the full for therapeutic manipulation can be therapeutic of novel T costimulatory pathways