Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

Yeo, Lorraine, Woodwyk, Alyssa, Sood, Sanjana, Lorenc, Anna, Eichmann, Martin, Pujol-Autonell, Irma, Melchiotti, Rosella, Slowera, Ania, Fidanis, Efthymios, Dolton, Garry M., Tungatt, Katie, Sewell, Andrew K., Heck, Susanne, Saxena, Alka, Beam, Craig A., and Peakman, Mark (2018) Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes. Journal of Clinical Investigation, 128. pp. 3460-3474.

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Abstract

In type 1 diabetes, cytotoxic CD8+ T cells with specificity for β cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β cell–reactive CD8+ T cells that are detectable in the circulation, and their relationship to β cell function, are not known. Here, we tracked multiple, circulating β cell–reactive CD8+ T cell subsets and measured β cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in β cell–specific effector memory CD8+ T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8+ T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer-specific protein of 37 kDa, and CD16, and reduced expression of CD28) compared with their CD57– counterparts, and network association modeling indicated that the dynamics of β cell–reactive CD57+ effector memory CD8+ T cell subsets were strongly linked. Thus, coordinated changes in circulating β cell–specific CD8+ T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

Item ID: 55251
Item Type: Article (Refereed Research - C1)
ISSN: 1558-8238
Funders: National Institute for Health Research (NIHR), St. Thomas' National Health Service Foundation, King's College, London (KCL), Juvenile Diabetes Research Foundation (JDRF), Innovative Medicines Initiative (IMI), European Federation of Pharmaceutical Industries and Associations (EF), Leona M. and Harry B. Helmsley Charitable Trust
Projects and Grants: JDRF 17-2013-583, IMI 115797 INNODIA
Date Deposited: 11 Sep 2018 02:58
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110703 Autoimmunity @ 50%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920104 Diabetes @ 100%
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