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 3

Gene and protein expression profiles indicate enhanced cytotoxic capability of CD57+ effector memory CD8+ T cells in type 1 diabetes patients.

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Gene and protein expression profiles indicate enhanced cytotoxic capabil...
(A) RNA sequencing of CD57+ and CD57– effector memory CD8+ T cells. The top 5% differentially expressed genes are shown. (B) Volcano plot showing all genes upregulated (blue dots) and downregulated (red dots) in CD57+ compared with CD57– effector memory CD8+ T cells. Genes with Benjamini-Hochberg adjusted P ≤ 0.05 and absolute log2 fold change greater than 1 were considered significant. Differential expression analysis was performed with the DESeq2 package in R. Horizontal dashed line, FDR = 0.05; vertical dashed line, log2(fold change) = 1. (C) Significantly enriched gene ontology terms represented within differentially expressed genes. Gene ontology enrichment was performed using the R package clusterProfiler, and ontologies with adjusted P ≤ 0.05 were considered significant. (D) Protein expression of key differentially expressed genes in PPI-specific CD57+ and CD57– effector memory CD8+ T cells assessed by flow cytometry (n = 5 type 1 diabetes subjects). Bars and error bars represent means ± SD. Mann-Whitney test, *P < 0.05, **P < 0.01. MFI, mean fluorescence intensity.