title: Overexpression of the Ctla-4 isoform lacking exons 2 and 3 causes autoimmunity.
abstract: CTLA-4 is a potent inhibitor of T cell activation, primarily upon binding to its costimulatory ligands (B7.1 and B7.2) expressed on APCs. However, variants of CTLA-4 can also function independently of B7 molecules. 1/4CTLA-4 is a highly conserved isoform encoded by exons 1 and 4 of the Ctla4 gene that lacks the ligand-binding and the transmembrane domains, and as yet, its function is not known. To investigate the function of 1/4CTLA-4, we generated transgenic (Tg) mice overexpressing this variant. Cytokine production by 1/4CTLA-4 Tg T cells was elevated compared with wild type T cells. The frequency of CD44(high) memory T cells in 1/4CTLA-4 Tg mice was increased, and as the mice aged, the frequency further increased. 1/4CTLA-4 Tg mice >1 y old had increased expression of T cell activation markers and developed spontaneous autoimmunity, including elevated production of autoantibodies. In contrast with young 1/4CTLA-4 Tg mice, aged 1/4CTLA-4 Tg mice had elevated frequencies of Foxp3(+) regulatory T cells, but the regulatory T cells from these mice were not able to inhibit colitis development. Collectively, these data suggest that the function of the 1/4CTLA-4 isoform is distinct from that of CTLA-4 in that it enhances T cell activation and promotes autoimmunity rather than inhibiting immune responses.
authors: Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115, USA.
authors: Sue M
authors: SM
authors: Liu
authors: Andrew P R
authors: AP
authors: Sutherland
authors: Zheng
authors: Z
authors: Zhang
authors: Daniel B
authors: DB
authors: Rainbow
authors: Francisco J
authors: FJ
authors: Quintana
authors: Alison M
authors: AM
authors: Paterson
authors: Arlene H
authors: AH
authors: Sharpe
authors: Mohamed
authors: M
authors: Oukka
authors: Linda S
authors: LS
authors: Wicker
authors: Vijay K
authors: VK
authors: Kuchroo
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005091:Exons / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D020033:Protein Isoforms