title: An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4(+) T cells.
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.
authors.affiliation: Department of Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA. along@benaroyaresearch.org
authors.forename: S A
authors.initials: SA
authors.lastname: Long
authors.forename: K
authors.initials: K
authors.lastname: Cerosaletti
authors.forename: J Y
authors.initials: JY
authors.lastname: Wan
authors.forename: J-C
authors.initials: JC
authors.lastname: Ho
authors.forename: M
authors.initials: M
authors.lastname: Tatum
authors.forename: S
authors.initials: S
authors.lastname: Wei
authors.forename: H G
authors.initials: HG
authors.lastname: Shilling
authors.forename: J H
authors.initials: JH
authors.lastname: Buckner
mesh_terms: D000328:Adult; D000483:Alleles; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D010641:Phenotype; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics* / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2