B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms

Masashi Watanabe, Ying Lu, Michael Breen and Richard J. Hodes ()
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Masashi Watanabe: Experimental Immunology Branch, National Cancer Institute
Ying Lu: Experimental Immunology Branch, National Cancer Institute
Michael Breen: Experimental Immunology Branch, National Cancer Institute
Richard J. Hodes: Experimental Immunology Branch, National Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Here we show that B7-CD28 co-stimulation and B7 expression by specific antigen-presenting cell (APC) types are required for clonal deletion and for regulatory T (Treg) cell generation from endogenous tissue-restricted antigen (TRA)-specific thymocytes. While B7-CD28 interaction is required for both clonal deletion and Treg induction, these two processes differ in their CD28 signaling requirements and in their dependence on B7-expressing dendritic cells, B cells, and thymic epithelial cells. Meanwhile, defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. Our findings thus reveal a function of B7-CD28 co-stimulation in shaping the T cell repertoire and limiting autoimmunity through both thymic clonal deletion and Treg cell generation.

Date: 2020
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DOI: 10.1038/s41467-020-20070-x

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