CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion

Immunity. 2015 Nov 17;43(5):896-908. doi: 10.1016/j.immuni.2015.10.011. Epub 2015 Nov 10.


Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This might explain why autoimmunity is often tissue-specific, and it offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • Autoimmunity / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / immunology
  • Forkhead Transcription Factors / immunology
  • Immune Tolerance / immunology*
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory / immunology*


  • Autoantigens
  • Cancer Vaccines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse