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A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 ( PTPN22 ), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- ( p &lt; 0.05) and 3.6-fold ( p &lt; 0.001) more PTPN22 transcripts in resting CD4 + memory and regulatory T cells (Tregs), respectively, over naive CD4 + T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4 + T cells, TCR signaling and activation were blunted by LYP-620R ( p &lt; 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3- and anti-CD28-coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4 + T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4 + T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders.

Overexpression of the PTPN22 Autoimmune Risk Variant LYP-620W Fails to Restrain Human CD4+ T Cell Activation