Follicular helper T cell signature in type 1 diabetes
Rupert Kenefeck, … , Parth Narendran, Lucy S.K. Walker
Rupert Kenefeck, … , Parth Narendran, Lucy S.K. Walker
Published December 8, 2014
Citation Information: J Clin Invest. 2015;125(1):292-303. https://doi.org/10.1172/JCI76238.
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Research Article Immunology

Follicular helper T cell signature in type 1 diabetes

Abstract

The strong genetic association between particular HLA alleles and type 1 diabetes (T1D) indicates a key role for CD4+ T cells in disease; however, the differentiation state of the responsible T cells is unclear. T cell differentiation originally was considered a dichotomy between Th1 and Th2 cells, with Th1 cells deemed culpable for autoimmune islet destruction. Now, multiple additional T cell differentiation fates are recognized with distinct roles. Here, we used a transgenic mouse model of diabetes to probe the gene expression profile of islet-specific T cells by microarray and identified a clear follicular helper T (Tfh) cell differentiation signature. Introduction of T cells with a Tfh cell phenotype from diabetic animals efficiently transferred diabetes to recipient animals. Furthermore, memory T cells from patients with T1D expressed elevated levels of Tfh cell markers, including CXCR5, ICOS, PDCD1, BCL6, and IL21. Defects in the IL-2 pathway are associated with T1D, and IL-2 inhibits Tfh cell differentiation in mice. Consistent with these previous observations, we found that IL-2 inhibited human Tfh cell differentiation and identified a relationship between IL-2 sensitivity in T cells from patients with T1D and acquisition of a Tfh cell phenotype. Together, these findings identify a Tfh cell signature in autoimmune diabetes and suggest that this population could be used as a biomarker and potentially targeted for T1D interventions.

Authors

Rupert Kenefeck, Chun Jing Wang, Tauseef Kapadi, Lukasz Wardzinski, Kesley Attridge, Louise E. Clough, Frank Heuts, Alexandros Kogimtzis, Sapna Patel, Miranda Rosenthal, Masahiro Ono, David M. Sansom, Parth Narendran, Lucy S.K. Walker

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Figure 1

Islet-specific conventional T cells in the PanLNs of DO11 RIP-mOVA mice have a Tfh gene signature.

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Islet-specific conventional T cells in the PanLNs of DO11 RIP-mOVA mice ...
Microarray analysis of sorted islet-specific conventional T cells or Tregs (CD4+DO11+CD25–CD69–, CD4+DO11+CD25–CD69+, CD4+DO11+CD25+CD69–, CD4+DO11+CD25+CD69+) from the PanLNs or inguinal LNs (LN) of 6-week-old DO11 RIP-mOVA mice. (A) Heat map analysis of microarray data (3–6 replicates for each sort) using a panel of Tfh cell signature genes. PanLN T cell samples cluster together and show strong upregulation of Tfh cell genes. (B) PCA and CCA analysis incorporating a publically available Tfh data set to derive a “Tfh-ness” score. Sample score plot of PCA and CCA biplots, showing sample scores (circles) and explanatory variables (arrows, obtained from a publically available Tfh data set, GSE40068), are shown. (C) Plot of “Tfh-ness” score derived from CCA analysis of the 2 sets of microarray data in B, showing relative correlations of samples to the Tfh population. Differentially expressed genes in the Tfh data set were used (n = 200). Gray line indicates the center of sample scores (0).