title: Treg and CTLA-4: two intertwining pathways to immune tolerance.
abstract: 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.
authors.affiliation: Institute of Immunity & Transplantation, University College London Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Electronic address: lucy.walker@ucl.ac.uk.
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
chemical_list: D019138:Antibodies, Blocking; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
keywords: CD4 T cells; CTLA-4; Foxp3; Immune regulation; Tolerance; Treg