Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes
Lorraine Yeo, Alyssa Woodwyk, Sanjana Sood, Anna Lorenc, Martin Eichmann, Irma Pujol-Autonell, Rosella Melchiotti, Ania Skowera, Efthymios Fidanis, Garry M. Dolton, Katie Tungatt, Andrew K. Sewell, Susanne Heck, Alka Saxena, Craig A. Beam, Mark Peakman
Lorraine Yeo, Alyssa Woodwyk, Sanjana Sood, Anna Lorenc, Martin Eichmann, Irma Pujol-Autonell, Rosella Melchiotti, Ania Skowera, Efthymios Fidanis, Garry M. Dolton, Katie Tungatt, Andrew K. Sewell, Susanne Heck, Alka Saxena, Craig A. Beam, Mark Peakman
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Research Article Autoimmunity Immunology

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

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.

Authors

Lorraine Yeo, Alyssa Woodwyk, Sanjana Sood, Anna Lorenc, Martin Eichmann, Irma Pujol-Autonell, Rosella Melchiotti, Ania Skowera, Efthymios Fidanis, Garry M. Dolton, Katie Tungatt, Andrew K. Sewell, Susanne Heck, Alka Saxena, Craig A. Beam, Mark Peakman

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Figure 2

β Cell–specific and virus-specific CD8+ T cell subsets are significantly correlated with longitudinal C-peptide change.

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β Cell–specific and virus-specific CD8+ T cell subsets are significantly...
(A) Five β cell–specific CD8+ T cell subsets are positively correlated with C-peptide. Additionally, when data are pooled from all β cell–specific (PPI-, InsB-, GAD-, IA2-, and GAD-specific) CD8+ T cells, the CD57+ effector memory CD8+ T subset (“Pooled β cell–specific CD57+ EM”) is positively correlated with C-peptide. (B) Nine virus-specific CD8+ T cell subsets are correlated with longitudinal C-peptide change. Seven of nine are negatively correlated; two are positively correlated. The predicted log C-peptide change from baseline per 1% increase in each T cell subset is plotted. Thirty-eight subjects were studied, and relationships between T cell and C-peptide changes from baseline across time were analyzed with mixed-effects general linear models. To understand the variance of these data, note that the P values indicate the standard error, and for P < 0.05, a 95% confidence interval would not include the value zero. CM, central memory; TM, transitional memory; EM, effector memory; TE, terminal effector. Relationships between T cell and C-peptide changes from baseline across time were analyzed with mixed-effects general linear models. P < 0.05 (indicated by dotted horizontal line) was regarded as significant.