The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals

Nat Immunol. 2014 Sep;15(9):875-883. doi: 10.1038/ni.2958. Epub 2014 Aug 10.


T cells must be tolerant of self antigens to avoid autoimmunity but responsive to foreign antigens to provide protection against infection. We found that in both naive T cells and effector T cells, the tyrosine phosphatase PTPN22 limited signaling via the T cell antigen receptor (TCR) by weak agonists and self antigens while not impeding responses to strong agonist antigens. T cells lacking PTPN22 showed enhanced formation of conjugates with antigen-presenting cells pulsed with weak peptides, which led to activation of the T cells and their production of inflammatory cytokines. This effect was exacerbated under conditions of lymphopenia, with the formation of potent memory T cells in the absence of PTPN22. Our data address how loss-of-function PTPN22 alleles can lead to the population expansion of effector and/or memory T cells and a predisposition to human autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Antigen-Presenting Cells / immunology
  • Autoimmunity / immunology*
  • Lymphocyte Activation / immunology
  • Mice
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / immunology*
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*


  • Receptors, Antigen, T-Cell
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Ptpn22 protein, mouse