Follicular helper T cell signature in type 1 diabetes
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
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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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 7

IL-21–producing CD4+ T cells are elevated in patients with T1D and correlate strongly with the proportion of CXCR5+ cells.

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IL-21–producing CD4+ T cells are elevated in patients with T1D and corre...
(A) Frequencies of CD4 T cells producing the indicated cytokines following 14-hour anti-CD3 stimulation of cells from patients with T1D (n = 22) and healthy controls (n = 13). Box and whisker plots show the median, interquartile range, and 10th to 90th percentile. (B) Frequencies of cells producing a defined combination of cytokines (as shown) within the stimulated CD4+ T cell population in patients with T1D (n = 22) and healthy controls (n = 13). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Bars show the mean, and error bars show the SEM. (C) Distribution of cytokine production within the CD4+ IL-21–producing population showing that the majority of IL-21 producers coexpress TNF-α and/or IFN-γ. Data show values averaged from 22 individuals. Unlabeled segments comprise <1.5%. (D) Correlation between the frequency of IL-21+ CD4+ T cells following anti-CD3 stimulation as in A and fresh ex vivo CXCR5 expression in patients with T1D (n = 13). (E) Populations of naive (CD4+CD45RA+CXCR5–), memory CXCR5– (CD4+CD45RA–CXCR5–), and memory CXCR5+ (CD4+CD45RA–CXCR5+) cells were sorted by FACS from healthy controls and stimulated for 16 hours with anti-CD3/anti-CD28 beads. The proportion of cells expressing the cytokines IL-21, IL-4, IFN-γ, and IL-17 was then assessed. Bars show the mean, and error bars show the SEM.