Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes

Boldison, Joanne, Long, Anna E., Aitken, Rachel J., Wilson, Isabel V., Megson, Clare, Hanna, Stephanie J., Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Gillespie, Kathleen M. 2022. Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes. Diabetologia 65 , 343–355. 10.1007/s00125-021-05595-0

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Abstract

Aims/hypothesis Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31–72 years), followed up for 18–32 years. Methods Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. Results Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. Conclusions/interpretations We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Springer
ISSN:	0012-186X
Date of First Compliant Deposit:	18 November 2021
Date of Acceptance:	26 August 2021
Last Modified:	08 May 2023 06:42
URI:	https://orca.cardiff.ac.uk/id/eprint/145603

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