title: Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood.
abstract: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4(+)Foxp3(+) Treg cells. However, T cells from CTLA-4-deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4-deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden;
authors.forename: Katrin
authors.initials: K
authors.lastname: Klocke
authors.affiliation: Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan kajsa.wing@ki.se shimon@ifrec.osaka-u.ac.jp.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden;
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden; kajsa.wing@ki.se shimon@ifrec.osaka-u.ac.jp.
authors.forename: Kajsa
authors.identifier: http://orcid.org/0000-0001-7744-4847
authors.initials: K
authors.lastname: Wing
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology; D001327:Autoimmune Diseases / Q000209:etiology*; D015551:Autoimmunity; D060908:CTLA-4 Antigen / Q000172:deficiency*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen
keywords: CTLA-4; Foxp3; autoimmunity; regulatory T cells; tolerance