Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3.sup.+IL-17.sup.+ cells

• Published in: Genes and immunity Vol. 18; no. 1; pp. 15 - 21
• Main Authors: Marwaha, A K, Panagiotopoulos, C, Biggs, C M, Staiger, S, Del Bel, K L, Hirschfeld, A F, Priatel, J J, Turvey, S.E, Tan, R
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01.01.2017
• Subjects: Development and progression; Genetic aspects; Health aspects; Interleukins; Suppressor cells; Type 1 diabetes; Canada
• DOI: 10.1038/gene.2016.44
• ISSN: 1466-4879

T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3.sup.lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3.sup.+IL-17.sup.+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3.sup.+IL-17.sup.+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.