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

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 previousl...

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Published inGenes 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
LanguageEnglish
Published London Nature Publishing Group UK 01.01.2017
Nature Publishing Group
Subjects
13/31
38
631/208/728
631/250/2152
Biomarkers - metabolism
Biomedical and Life Sciences
Biomedicine
Cancer Research
Comparative analysis
Cytokines
Diabetes
Diabetes mellitus (insulin dependent)
Diabetes Mellitus, Type 1 - diagnosis
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
Diagnosis
Flow Cytometry
Forkhead Transcription Factors - genetics
Foxp3 protein
Gene Expression
Genes
Genetic aspects
Genotype
Genotype & phenotype
Genotyping
Health aspects
Helper cells
Human Genetics
Humans
Immune Tolerance
Immunological tolerance
Immunology
Immunoregulation
Inflammation
Interleukin 17
Interleukin 2
Interleukin 2 receptors
Interleukin-17 - genetics
Interleukin-2 - genetics
Interleukins
Lymphocytes
Lymphocytes T
original-article
Pathogenesis
Pathology
Pediatrics
Phenotypes
Phosphorylation
Physiological aspects
Prognosis
Signal Transduction
Single nucleotide polymorphisms
Single-nucleotide polymorphism
Suppressor cells
T-Lymphocytes, Regulatory - immunology
Th17 Cells
Type 1 diabetes
Variance analysis
Canada
Qatar
British Columbia Canada
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Abstract 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.
AbstractList 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.
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 FOXP3lo 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.
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. Genes and Immunity (2017) 18, 15-21; doi: 10.1038/gene.2016.44; published online 5 January 2017
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 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.
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 FOXP3lo 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.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 FOXP3lo 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.
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.
Audience Academic
Author Turvey, S E
Marwaha, A K
Del Bel, K L
Priatel, J J
Hirschfeld, A F
Biggs, C M
Panagiotopoulos, C
Staiger, S
Tan, R
AuthorAffiliation 2 Department of Pediatrics, University of British Columbia and Endocrine and Diabetes Unit, British Columbia Children’s Hospital, Vancouver, BC, Canada
4 Department of Pathology, Sidra Medical and Research Center, Doha, Qatar
1 Department of Pathology and Laboratory Medicine, University of British Columbia and Child and Family Research Institute, British Columbia Children’s Hospital, Vancouver, BC, Canada
3 Department of Pediatrics, University of British Columbia Division of Allergy and Immunology, Vancouver, BC, Canada
5 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Doha, Qatar
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PublicationTitle Genes and immunity
PublicationTitleAbbrev Genes Immun
PublicationTitleAlternate Genes Immun
PublicationYear 2017
Publisher Nature Publishing Group UK
Nature Publishing Group
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Snippet T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs...
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StartPage 15
SubjectTerms 13/31
38
631/208/728
631/250/2152
Biomarkers - metabolism
Biomedical and Life Sciences
Biomedicine
Cancer Research
Comparative analysis
Cytokines
Diabetes
Diabetes mellitus (insulin dependent)
Diabetes Mellitus, Type 1 - diagnosis
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
Diagnosis
Flow Cytometry
Forkhead Transcription Factors - genetics
Foxp3 protein
Gene Expression
Genes
Genetic aspects
Genotype
Genotype & phenotype
Genotyping
Health aspects
Helper cells
Human Genetics
Humans
Immune Tolerance
Immunological tolerance
Immunology
Immunoregulation
Inflammation
Interleukin 17
Interleukin 2
Interleukin 2 receptors
Interleukin-17 - genetics
Interleukin-2 - genetics
Interleukins
Lymphocytes
Lymphocytes T
original-article
Pathogenesis
Pathology
Pediatrics
Phenotypes
Phosphorylation
Physiological aspects
Prognosis
Signal Transduction
Single nucleotide polymorphisms
Single-nucleotide polymorphism
Suppressor cells
T-Lymphocytes, Regulatory - immunology
Th17 Cells
Type 1 diabetes
Variance analysis
Title Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells
URI https://link.springer.com/article/10.1038/gene.2016.44
https://www.ncbi.nlm.nih.gov/pubmed/28053319
https://www.proquest.com/docview/1861813966
https://www.proquest.com/docview/2615530274
https://www.proquest.com/docview/1855786869
https://pubmed.ncbi.nlm.nih.gov/PMC5843473
Volume 18
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