title: Ctla-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity.
abstract: The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3(+) regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3(+) cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas autoimmunity.
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Schmidt
authors.forename: Chun Jing
authors.initials: CJ
authors.lastname: Wang
authors.forename: Gemma A
authors.initials: GA
authors.lastname: Ryan
authors.forename: Louise E
authors.initials: LE
authors.lastname: Clough
authors.forename: Omar S
authors.initials: OS
authors.lastname: Qureshi
authors.forename: Margaret
authors.initials: M
authors.lastname: Goodall
authors.forename: Abul K
authors.initials: AK
authors.lastname: Abbas
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell