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

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

Author information

1
Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Charlestown, MA 02129, USA.
2
Howard Hughes Medical Institute, Ludwig Center, and Immunology Program; Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
3
Division of Infectious Diseases and Perinatal Institute; Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
4
Division of Neonatology and Pediatric Molecular and Personalized Medicine Program; University of Rochester, Rochester, NY 14642, USA.
5
TWINCORE - Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany.
6
Center for Immunology and Inflammatory Diseases, and Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital; and Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: jjmoon@mgh.harvard.edu.

Abstract

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.

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PMID:
26572061
PMCID:
PMC4654997
DOI:
10.1016/j.immuni.2015.10.011
[Indexed for MEDLINE]
Free PMC Article

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