An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells

SA Long, K Cerosaletti, JY Wan, JC Ho, M Tatum… - Genes & …, 2011 - nature.com
SA Long, K Cerosaletti, JY Wan, JC Ho, M Tatum, S Wei, HG Shilling, JH Buckner
Genes & Immunity, 2011nature.com
Abstract The IL-2/IL-2R signaling pathway has an important role in autoimmunity. Several
genes identified in genome-wide association (GWA) studies encode proteins in the IL-2/IL-
2R signaling cascade that are associated with autoimmune diseases. One of these, PTPN2,
encodes a protein tyrosine phosphatase that is highly expressed in T cells and regulates
cytokine signaling. An intronic risk allele in PTPN2, rs1893217 (C), correlated with
decreased IL-2R signaling in CD4+ T cells as measured by phosphorylation of STAT5 …
Abstract
The IL-2/IL-2R signaling pathway has an important role in autoimmunity. Several genes identified in genome-wide association (GWA) studies encode proteins in the IL-2/IL-2R signaling cascade that are associated with autoimmune diseases. One of these, PTPN2, encodes a protein tyrosine phosphatase that is highly expressed in T cells and regulates cytokine signaling. An intronic risk allele in PTPN2, rs1893217 (C), correlated with decreased IL-2R signaling in CD4+ T cells as measured by phosphorylation of STAT5 (phosphorylated STAT5 (pSTAT5)). We modeled an additive single nucleotide polymorphism (SNP) genotype, in which each copy of the risk allele conferred a decrease in IL-2R signaling (P= 4.4× 10− 8). Decreased pSTAT5 impacted IL-2Rβ chain signaling resulting in reduced FOXP3 expression in activated cells. This phenotype was not due to overt differences in expression of the IL-2R, molecules in the IL-2R signaling cascade or defects in STAT5. However, the rs1893217 (C) risk variant did correlate with decreased PTPN2 expression in CD4+ CD45RO T cells (P= 0.0002). Thus, the PTPN2rs1893217 (C) risk allele associated with reduced pSTAT5 in response to IL-2 and reduced PTPN2 expression. Together, these data suggest that decreased expression of PTPN2 may indirectly modulate IL-2 responsiveness. These findings, identified through genotype/phenotype relationships, may lead to identification of novel mechanisms underlying dysregulation of cytokine signaling in autoimmunity.
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