Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for humanautoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays arole in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. Onemodel holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/orthymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated micein which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes undercontrol of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling,thus modeling a ''gain-of-function'' of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterationsof thymic negative selection and no anomalies in thymic output of CD4+Foxp3+ Treg were detected in these mice. Lckpromoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in diseaseseverity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4+ T cells. Our data suggestthat a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and thatLYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk ofautoimmunity.