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.
Emory Transplant Center, Atlanta, GA.
S M
SM
Krummey
M L
ML
Ford
D000818:Animals; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D016377:Organ Transplantation; D013601:T-Lymphocytes / Q000276:immunology*
D060908:CTLA-4 Antigen
T cell biology; basic (laboratory) research; costimulation; immune modulation; immunobiology; immunosuppression; science; signaling; signaling pathways