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

作者：Krummey S M; Ford M L^*

来源：American Journal of Transplantation, 2014, 14(12): 2685-2690.

DOI：10.1111/ajt.12938

• basic (laboratory) research
• science
• immunobiology
• immunosuppression
• immune modulation
• T cell biology
• signaling
• signaling pathways
• costimulation

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.
While the coinhibitory receptor CTLA-4 is well established as an important mediator of tolerance, the authors describe recent discoveries that significantly deepen our understanding of mechanisms of CTLA-4 function.

• 出版日期2014-12