title: Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients.
abstract: IL-2 receptor (IL-2R) signaling is essential for optimal stability and function of CD4(+)CD25(hi)FOXP3(+) regulatory T cells (Treg); a cell type that plays an integral role in maintaining tolerance. Thus, we hypothesized that decreased response to IL-2 may be a common phenotype of subjects who have autoimmune diseases associated with variants in the IL2RA locus, including T1D and MS, particularly in cells expressing the high affinity IL-2R alpha chain (IL-2RA or CD25). To examine this question we used phosphorylation of STAT5 (pSTAT5) as a downstream measure of IL-2R signaling, and found a decreased response to IL-2 in CD4(+)CD25(hi) T cells of T1D and MS, but not SLE patients. Since the IL2RArs2104286 haplotype is associated with T1D and MS, we measured pSTAT5 in controls carrying the rs2104286 risk haplotype to test whether this variant contributed to reduced IL-2 responsiveness. Consistent with this, we found decreased pSTAT5 in subjects carrying the rs2104286 risk haplotype. Reduced IL-2R signaling did not result from lower CD25 expression on CD25(hi) cells; instead we detected increased CD25 expression on naive Treg from controls carrying the rs2104286 risk haplotype, and subjects with T1D and MS. However the rs2104286 risk haplotype correlated with increased soluble IL-2RA levels, suggesting that shedding of the IL-2R may account in part for the reduced IL-2R signaling associated with the rs2104286 risk haplotype. In addition to risk variants in IL2RA, we found that the T1D-associated risk variant of PTPN2rs1893217 independently contributed to diminished IL-2R signaling. However, even when holding genotype constant at IL2RA and PTPN2, we still observed a significant signaling defect in T1D and MS patients. Together, these data suggest that multiple mechanisms converge in disease leading to decreased response to IL-2, a phenotype that may eventually lead to loss of tolerance and autoimmunity.
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Cerosaletti
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Anya
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Katharine
authors.initials: K
authors.lastname: Schwedhelm
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Frank
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Tatum
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Shan
authors.initials: S
authors.lastname: Wei
authors.affiliation: Bioinformatics, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Whalen
authors.affiliation: Diabetes Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Carla
authors.initials: C
authors.lastname: Greenbaum
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Mariko
authors.initials: M
authors.lastname: Kita
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: Jane
authors.initials: J
authors.lastname: Buckner
authors.affiliation: Translational Research, Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
authors.forename: S Alice
authors.initials: SA
authors.lastname: Long
mesh_terms: D000328:Adult; D000483:Alleles; D015551:Autoimmunity / Q000187:drug effects / Q000235:genetics*; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012995:Solubility; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2