Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood

Author:

Klocke Katrin,Sakaguchi Shimon,Holmdahl Rikard,Wing KajsaORCID

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.

Funder

Vetenskapsrådet

Ake Wibergs Stiftelse

Knut och Alice Wallenbergs Stiftelse

Ministry of Education, Culture, Sports, Science, and Technology

Core Research for Evolutional Science and Technology, Japan Science and Technology Agency

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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