Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes
Lorraine Yeo, … , Craig A. Beam, Mark Peakman
Lorraine Yeo, … , Craig A. Beam, Mark Peakman
Published May 31, 2018
Citation Information: J Clin Invest. 2018;128(8):3460-3474. https://doi.org/10.1172/JCI120555.
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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 5

Visualization of the relationships between CD8+ T cell subsets over time.

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Visualization of the relationships between CD8+ T cell subsets over time...
Pairwise correlations between CD8+ T cell subsets are displayed in a “network association plot” in which each T cell subset is represented by a node and nodes are connected by lines whose width is proportional to the strength of the correlation. Green lines indicate positive correlations and red lines indicate negative correlations. Nodes are also clustered on the strength of their correlations. Each CD8+ T cell subset is colored uniquely: naive (N), yellow; stem cell memory (SCM), gray; central memory (CM), light green; transitional memory (TM), dark green; effector memory (EM)/CD57+ effector memory (CD57+ EM)/CD57– effector memory (CD57– EM), blue; pre–terminal effector (pre-TE), orange; terminal effector (TE), red; total tetramer-positive CD8+ T cell populations, white. The dashed oval highlights strong correlations between β cell–specific CD57+ effector memory CD8+ T cell subsets.