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Braking Bad: Novel Mechanisms of CTLA‐4 Inhibition of T Cell Responses

The coinhibitory receptor cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) is a master regulator of T cell responses and its function is critical in models of transplant tolerance. The CD28/CTLA‐4 pathway is also an important therapeutic target, as the costimulation blocker belatacept was recently approved for use following renal transplantation. While the traditional model of CTLA‐4 coinhibition focuses on its ability to directly counteract CD28 costimulation, recently this paradigm has significantly broadened. Recent work has uncovered the ability of CTLA‐4 to act as a cell‐extrinsic coinhibitory molecule on CD4+ T cell effectors. While it has been appreciated that CTLA‐4 is required for FoxP3+ regulatory T cell (Treg) suppression, current studies have elucidated important differences in the function of CTLA‐4 on Tregs compared to effectors. CTLA‐4 expression patterns also differ by T cell subset, with Th17 cells expressing significantly higher levels of CTLA‐4. Thus, in contrast to the traditional model of CTLA‐4 as a negative receptor to counter CD28 costimulation, recent work has begun to define CTLA‐4 as a global regulator of T cell responses with subset‐specific functions. Future studies must continue to uncover the molecular mechanisms that govern CTLA‐4 function. These novel findings have implications for novel strategies to maximize the regulatory potential of CTLA‐4 during allogeneic T cell responses.