The tyrosine phosphatase Ptpn22 discriminates weak, self-peptide from strong agonist T cell receptor signals

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 and effector T cells, the tyrosine phosphatase, Ptpn22 limits T cell receptor signaling by weak agonist and self-antigens, while not impeding responses to strong agonist antigens. T cells lacking Ptpn22 show enhanced conjugate formation with antigen presenting cells pulsed with weak peptides, leading to their activation and production of inflammatory cytokines. This effect is exacerbated under conditions of lymphopenia with the formation of potent memory T cells in the absence of Ptpn22. These data address how loss of function PTPN22 alleles can lead to expansion of effector/memory T cells and a predisposition to human autoimmunity.