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

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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-deficientmice. 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-4deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of proteininduced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cellmediated suppression.

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Klocke, K., Sakaguchi, S., Holmdahl, R., & Wing, K. (2016). Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proceedings of the National Academy of Sciences of the United States of America, 113(17). https://doi.org/10.1073/pnas.1603892113

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