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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.

Original publication

DOI

10.1084/jem.20141030

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

14/09/2015

Volume

212

Pages

1603 - 1621

Addresses

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.

Keywords

Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Encephalomyelitis, Autoimmune, Experimental, Tamoxifen, Interleukin-10, Age Factors, Autoimmunity, Gene Deletion, Amino Acid Sequence, Molecular Sequence Data, T-Lymphocytes, Regulatory, CTLA-4 Antigen, Disease Resistance