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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dc.contributor.authorBediaga, N.G.
dc.contributor.authorGarnham, A.L.
dc.contributor.authorNaselli, G.
dc.contributor.authorBandala-Sanchez, E.
dc.contributor.authorStone, N.L.
dc.contributor.authorCobb, J.
dc.contributor.authorHarbison, J.E.
dc.contributor.authorWentworth, J.M.
dc.contributor.authorZiegler, A.G.
dc.contributor.authorCouper, J.J.
dc.contributor.authorSmyth, G.K.
dc.contributor.authorHarrison, L.C.
dc.date.issued2022
dc.descriptionThis article contains supplementary material online at https://doi.org/10.2337/figshare.17185898.
dc.description.abstractType 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.
dc.description.statementofresponsibilityNaiara 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
dc.identifier.citationDiabetes, 2022; 71(3):566-577
dc.identifier.doi10.2337/db21-0612
dc.identifier.issn0012-1797
dc.identifier.issn1939-327X
dc.identifier.orcidCouper, J.J. [0000-0003-4448-8629]
dc.identifier.urihttps://hdl.handle.net/2440/137004
dc.language.isoen
dc.publisherAmerican Diabetes Association
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1150425
dc.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:// www.diabetesjournals.org/journals/pages/license.
dc.source.urihttps://doi.org/10.2337/db21-0612
dc.subjectIslets of Langerhans
dc.subjectB-Lymphocytes
dc.subjectKiller Cells, Natural
dc.subjectCD4-Positive T-Lymphocytes
dc.subjectCD8-Positive T-Lymphocytes
dc.subjectChromatin
dc.subjectHumans
dc.subjectDiabetes Mellitus, Type 1
dc.subjectDisease Progression
dc.subjectGenetic Predisposition to Disease
dc.subjectSequence Analysis, RNA
dc.subjectAutoimmunity
dc.subjectCytotoxicity, Immunologic
dc.subjectGene Expression Regulation
dc.subjectAdolescent
dc.subjectChild
dc.subjectChild, Preschool
dc.subject.meshIslets of Langerhans
dc.subject.meshB-Lymphocytes
dc.subject.meshKiller Cells, Natural
dc.subject.meshCD4-Positive T-Lymphocytes
dc.subject.meshCD8-Positive T-Lymphocytes
dc.subject.meshChromatin
dc.subject.meshHumans
dc.subject.meshDiabetes Mellitus, Type 1
dc.subject.meshDisease Progression
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshSequence Analysis, RNA
dc.subject.meshAutoimmunity
dc.subject.meshCytotoxicity, Immunologic
dc.subject.meshGene Expression Regulation
dc.subject.meshAdolescent
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.titleCytotoxicity-related gene expression and chromatin accessibility define a subset of CD4+ T cells that mark progression to type 1 diabetes.
dc.typeJournal article
pubs.publication-statusPublished

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