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Follicular helper T cell signature in type 1 diabetes
Kenefeck, R Wang, CJ Kapadi, T Wardzinski, L Attridge, Kesley Clough, LE Heuts, F Kogimtzis, A Patel, S Rosenthal, M
Kenefeck, R
Wang, CJ
Kapadi, T
Wardzinski, L
Attridge, Kesley
Clough, LE
Heuts, F
Kogimtzis, A
Patel, S
Rosenthal, M
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Epub Date
Issue Date
2014-12-08
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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.
Citation
Kenefeck, R., Wang, C. J., Kapadi, T., Wardzinski, L. Attridge, K. et. al. (2014) Follicular helper T cell signature in type 1 diabetes, Journal of Clinical Investigation, 125(1), pp. 292–303.
Research Unit
DOI
PubMed ID
25485678
PubMed Central ID
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Type
Journal article
Language
en
Description
Series/Report no.
ISSN
0021-9738
EISSN
1558-8238
ISBN
ISMN
Gov't Doc #
Sponsors
This work was funded by an MRC Senior Fellowship (to L.S.K. Walker), a project grant from JDRF (to L.S.K. Walker and P. Narendran), and a studentship from Diabetes UK (to L.S.K. Walker and P. Narendran). L. Wardzinski and A. Kogimtzis were supported by a Wellcome Trust project grant (to L.S.K. Walker). M. Ono is a BBSRC David Philips fellow.