Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease

Abstract

Genome-wide association studies (GWAS) have identified a large number of SNPs that are linked to human autoimmune diseases. However, the functional consequences of most of these genetic variations remain undefined. T cell protein tyrosine phosphatase (TCPTP, which is encoded by PTPN2) is a JAK/STAT and growth factor receptor phosphatase that has been linked to the pathogenesis of type 1 diabetes, rheumatoid arthritis, and Crohn's disease by GWAS. In this issue of the JCI, Wiede and colleagues have generated a T cell-specific deletion of TCPTP and identified a novel role for this phosphatase as a negative regulator of TCR signaling. These data provide new insight as to how noncoding PTPN2 SNPs identified in GWAS could drive human autoimmune diseases.

Figure 1. Dual regulatory functions for TCPTP in T cells.

TCPTP, the protein encoded by the PTPN2 gene, has previously been shown to target JAK1/3 and STAT5a/b downstream of IL-2 receptor signaling as well as other cytokine pathways. In this issue of the JCI, Wiede and colleagues identify a new role for TCPTP as a negative regulator of TCR signaling through its ability to dephosphorylate the activation loop tyrosine of the SFK Lck (Y394) (4).