title: Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity.
abstract: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell responses. Germline Ctla4 deficiency is lethal, making investigation of the function of CTLA-4 on mature T cells challenging. To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated Ctla4 in adult mice. We show that, in contrast to germline knockout mice, deletion of Ctla4 during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and does not lead to increased resistance to MC38 tumors. Deletion of Ctla4 during adulthood was accompanied by activation and expansion of both conventional CD4(+)Foxp3(-) (T conv) and regulatory Foxp3(+) (T reg cells) T cell subsets; however, deletion of CTLA-4 on T reg cells was necessary and sufficient for protection from EAE. CTLA-4 deleted T reg cells remained functionally suppressive. Deletion of Ctla4 on T reg cells alone or on all adult T cells led to major changes in the Ctla4 sufficient T conv cell compartment, including up-regulation of immunoinhibitory molecules IL-10, LAG-3 and PD-1, thereby providing a compensatory immunosuppressive mechanism. Collectively, our findings point to a profound role for CTLA-4 on T reg cells in limiting their peripheral expansion and activation, thereby regulating the phenotype and function of T conv cells.
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Paterson
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Lovitch
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sage
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Juneja
authors.affiliation: Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Trombley
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford OX3 9DU, England, UK.
authors.forename: Carolina V
authors.initials: CV
authors.lastname: Arancibia-Cárcamo
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94304.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Sloan-Kettering Institute for Cancer Research; Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.affiliation: Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 arlene_sharpe@hms.harvard.edu.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D016753:Interleukin-10 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D060908:CTLA-4 Antigen; C556062:IL10 protein, mouse; D013629:Tamoxifen; D016753:Interleukin-10