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

Genes Immun. 2011 Mar;12(2):116-25. doi: 10.1038/gene.2010.54. Epub 2010 Dec 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Autoimmunity / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Male
  • Phenotype
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism*
  • Receptors, Interleukin-2 / immunology*
  • Receptors, Interleukin-2 / metabolism*
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-2
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2