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

Genes & Immunity volume 12, pages 116–125 (2011)Cite this article

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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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Acknowledgements

We would like to thank Jerry Nepom, Pat Concannon and Paul Bollyky for critical review of this manuscript. We wish to acknowledge the staff of the JDRF Center for Translational Research and the Benaroya Research Institute Translational Research program for subject recruitment and sample management. This work was supported by grants from the JDRF (The Center for Translational Research at BRI), NIH (R01 DK072457), NIH (R03 DA027013), JDRF (33-2008-398) and a grant for biostatistical support through the University of Washington Northwest Institute for Genetic Medicine from Washington State Life Science Discovery Funds (grant 265508).

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  1. S A Long and K Cerosaletti: These authors contributed equally to this work.

Authors and Affiliations

  1. Benaroya Research Institute at Virginia Mason, Seattle, WA, USA

    S A Long, K Cerosaletti, J-C Ho, M Tatum, S Wei, H G Shilling & J H Buckner

  2. Center for Biomedical Statistics, Northwest Institute of Genetic Medicine, University of Washington, Seattle, WA, USA

    J Y Wan

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Correspondence to S A Long.

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Long, S., Cerosaletti, K., Wan, J. et al. An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells. Genes Immun 12, 116–125 (2011). https://doi.org/10.1038/gene.2010.54

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