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 8

Patients who respond poorly to IL-2 show an increased propensity to upregulate CXCR5.

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Patients who respond poorly to IL-2 show an increased propensity to upre...
(A) Sorted CD4+CD45RA+ naive T cells from patients with T1D were cultured for 5 days with anti-CD3/anti-CD28 beads in the presence or absence of IL-12. Plots show representative CXCR5 staining. The percentage of gated CXCR5+ cells is shown on the graph. (B) Graphs show CXCR5 MFI of 5 independent experiments in which naive T cells were cultured for 5 days as above with IL-12 and or IL-2 (n = 15). Box and whisker plots show the median, interquartile range, and 10th to 90th percentile. *P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001. U, untreated. (C) Relationship between CXCR5 induction and sensitivity of T cells to IL-2. CD4+ T cells from patients with T1D were treated with 100 U IL-2 for 10 minutes and then fixed and stained for phosphorylated STAT5 (pSTAT5). The percentage of pSTAT5+ is plotted against the proportion of CXCR5+ cells induced by culture in the presence of IL-12 (as in A and B) (n = 13).