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

Nat Commun. 2020 Dec 8;11(1):6264. doi: 10.1038/s41467-020-20070-x.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antigen-Presenting Cells / metabolism
  • Autoimmunity / physiology
  • B7-1 Antigen / metabolism*
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism*
  • Cell Differentiation / immunology
  • Central Tolerance*
  • Clonal Deletion*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Flow Cytometry
  • Gene Knock-In Techniques
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Thymocytes / physiology
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism

Substances

  • B7-1 Antigen
  • CD28 Antigens
  • Receptors, Antigen, T-Cell, alpha-beta