Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2685-2690 |
Number of pages | 6 |
Journal | American Journal of Transplantation |
Volume | 14 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2014 |
Externally published | Yes |
Keywords
- T cell biology
- basic (laboratory) research
- costimulation
- immune modulation
- immunobiology
- immunosuppression
- science
- signaling
- signaling pathways
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)