A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 ( ), 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 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 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- ( < 0.05) and 3.6-fold ( < 0.001) more 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 ( < 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.