Autoimmunity-associated LYP regulates T cell receptor signaling and thymus development (148.21)

Abstract

Abstract A single nucleotide polymorphism (SNP) in the PTPN22 gene, which encodes the lymphoid tyrosine phophatase LYP, is associated with increased risk of Rheumatoid Arthritis and other autoimmune diseases. LYP inhibits T cell receptor (TCR) signaling by dephosphorylation of Lck and Zap70. The disease associated LYP R620W (LypW) protein caused by the missense C1858T SNP in PTPN22 appears to exert “gain-of-function” effects upon TCR activation. Here we show that LypW negatively regulates TCR-induced intracellular Ca2+ flux, tyrosine phosphorylation, MAPK activation, and NFAT response element transactivation in Jurkat cells. The effects of LYP on TCR signaling are dependent on its enzymatic function. Studies from ptpn22−/− mice shows that PTPN22 regulates thymocyte positive selection. To evaluate effects of LypW expression on lymphocyte selection and function, we generated BAC transgenic mice bearing either the major human PTPN22 allele (LypR) or LypW. In contrast to intact positive selection in LypW H-Y TCR transgenic female mice, we observed impaired negative selection in LypW, but not LypR, H-Y male mice. These findings suggest that susceptibility to autoimmune diseases in LypW-carrying people may result from enhanced presence of autoreactive T cell in the peripheral repertoire, due to impaired thymocyte deletion. Together, our data suggest a thymic developmental mechanism whereby a “gain of function” Lyp variant can predispose to autoimmune disease.