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Cytotoxicity-related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells that Mark Progression to Type 1 Diabetes
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posted on 2022-01-10, 18:56 authored by 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, Leonard C. HarrisonType 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 at-risk children, associated with progression to islet
autoimmunity. We analysed gene expression by RNAseq in CD4+ and CD8+
T cells, NK cells and B cells, and chromatin accessibility by ATACseq 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 to five children
matched for sex, age and HLA-DR who had not progressed (‘Non-progressors). 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 Non-progressors. Flow
cytometry confirmed 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.