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

• Published in: Nature communications 2020-12, Vol.11 (1), p.6264-14, Article 6264
• Main Authors: Watanabe, Masashi, Lu, Ying, Breen, Michael, Hodes, Richard J.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/2; 13/21; 13/31; 631/250/21; 631/250/2152/1566/2493; 631/250/2152/569/2494; 631/250/516; 64; 64/60; Animals; Antigen-presenting cells; Antigen-Presenting Cells - metabolism; Antigens; Autoimmunity; Autoimmunity - physiology; B7 antigen; B7-1 Antigen - metabolism; CD28 antigen; CD28 Antigens - genetics; CD28 Antigens - metabolism; Cell activation; Cell Differentiation - immunology; Central Tolerance; Clonal Deletion; Dendritic cells; Encephalomyelitis, Autoimmune, Experimental - immunology; Epithelial cells; Flow Cytometry; Gene Knock-In Techniques; Humanities and Social Sciences; Immunological tolerance; Lymphocytes; Lymphocytes B; Lymphocytes T; Mice; Mice, Knockout; multidisciplinary; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Science; Science (multidisciplinary); Signal Transduction - immunology; Signaling; Stimulation; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Thymocytes; Thymocytes - physiology; Thymus; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20070-x

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. B7-CD28 co-stimulation is important for T cell activation and clonal expansion in the periphery. Here the authors show that, in mouse thymus, B7-CD28 differentially controls thymocyte clonal deletion and Treg induction, with distinct CD28 signaling domains and B7-expressing antigen presenting cells mediating these two processes.