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.