Treg and CTLA-4: two intertwining pathways to immune tolerance

J Autoimmun. 2013 Sep;45(100):49-57. doi: 10.1016/j.jaut.2013.06.006. Epub 2013 Jul 10.


Both the CTLA-4 pathway and regulatory T cells (Treg) are essential for the control of immune homeostasis. Their therapeutic relevance is highlighted by the increasing use of anti-CTLA-4 antibody in tumor therapy and the development of Treg cell transfer strategies for use in autoimmunity and transplantation settings. The CTLA-4 pathway first came to the attention of the immunological community in 1995 with the discovery that mice deficient in Ctla-4 suffered a fatal lymphoproliferative syndrome. Eight years later, mice lacking the critical Treg transcription factor Foxp3 were shown to exhibit a remarkably similar phenotype. Much of the debate since has centered on the question of whether Treg suppressive function requires CTLA-4. The finding that it does in some settings but not in others has provoked controversy and inevitable polarization of opinion. In this article, I suggest that CTLA-4 and Treg represent complementary and largely overlapping mechanisms of immune tolerance. I argue that Treg commonly use CTLA-4 to effect suppression, however CTLA-4 can also function in the non-Treg compartment while Treg can invoke CTLA-4-independent mechanisms of suppression. The notion that Foxp3 and CTLA-4 direct independent programs of immune regulation, which in practice overlap to a significant extent, will hopefully help move us towards a better appreciation of the underlying biology and therapeutic significance of these pathways.

Keywords: CD4 T cells; CTLA-4; Foxp3; Immune regulation; Tolerance; Treg.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Blocking / therapeutic use
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology*
  • Forkhead Transcription Factors / genetics
  • Humans
  • Immune Tolerance
  • Immunosuppression Therapy
  • Immunotherapy / methods*
  • Immunotherapy / trends
  • Lymphoproliferative Disorders / genetics
  • Mice
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation


  • Antibodies, Blocking
  • CTLA-4 Antigen
  • FOXP3 protein, human
  • Forkhead Transcription Factors