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

Dennis J. Wu, Wenbo Zhou, Sarah Enouz, Valeria Orrú, Stephanie M. Stanford, Christian J. Maine, Novella Rapini, Kristy Sawatzke, Isaac Engel, Edoardo Fiorillo, Linda A. Sherman, Mitch Kronenberg, Dietmar Zehn, Erik J Peterson, Nunzio Bottini

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control 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 alterations of thymic negative selection and no anomalies in thymic output of CD4+Foxp3+ Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4+ T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity.

Original languageEnglish (US)
Article numbere86677
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 3 2014

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