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

Autor: Marwaha AK; Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada., Panagiotopoulos C; Department of Pediatrics, University of British Columbia and Endocrine and Diabetes Unit, British Columbia Children's Hospital, Vancouver, BC, Canada., Biggs CM; Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada., Staiger S; Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada., Del Bel KL; Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada., Hirschfeld AF; Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada., Priatel JJ; Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada., Turvey SE; Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada., Tan R; Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada.; Department of Pathology, Sidra Medical and Research Center, Doha, Qatar.; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Doha, Qatar.
Jazyk: angličtina
Zdroj: Genes and immunity [Genes Immun] 2017 Jan; Vol. 18 (1), pp. 15-21. Date of Electronic Publication: 2017 Jan 05.
DOI: 10.1038/gene.2016.44
Abstrakt: 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 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 + IL-17 + 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 + IL-17 + cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.
Databáze: MEDLINE
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