Braking bad: Novel mechanisms of CTLA-4 inhibition of T cell responses

S. M. Krummey, M. L. Ford

Research output: Contribution to journalReview articlepeer-review

15 Scopus citations


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 languageEnglish (US)
Pages (from-to)2685-2690
Number of pages6
JournalAmerican Journal of Transplantation
Issue number12
StatePublished - Dec 1 2014
Externally publishedYes


  • 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)


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