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Type: Journal article
Title: Cytotoxicity-related gene expression and chromatin accessibility define a subset of CD4+ T cells that mark progression to type 1 diabetes.
Author: Bediaga, N.G.
Garnham, A.L.
Naselli, G.
Bandala-Sanchez, E.
Stone, N.L.
Cobb, J.
Harbison, J.E.
Wentworth, J.M.
Ziegler, A.G.
Couper, J.J.
Smyth, G.K.
Harrison, L.C.
Citation: Diabetes, 2022; 71(3):566-577
Publisher: American Diabetes Association
Issue Date: 2022
ISSN: 0012-1797
Statement of
Naiara G. Bediaga, Alexandra L. Garnham, Gaetano Naselli, Esther Bandala-Sanchez, Natalie L. Stone, Joanna Cobb, Jessica E. Harbison, John M. Wentworth, Annette-G. Ziegler, Jennifer J. Couper, Gordon K. Smyth, and Leonard C. Harrison
Abstract: Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (“progressors”) compared with five children matched for sex, age, and HLA-DR who had not progressed (“nonprogressors”). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.
Keywords: Islets of Langerhans
Killer Cells, Natural
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Diabetes Mellitus, Type 1
Disease Progression
Genetic Predisposition to Disease
Sequence Analysis, RNA
Cytotoxicity, Immunologic
Gene Expression Regulation
Child, Preschool
Description: This article contains supplementary material online at
Rights: © 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://
DOI: 10.2337/db21-0612
Grant ID:
Appears in Collections:South Australian Immunogenomics Cancer Institute (SAIGENCI) publications

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