IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients.

Ricardo C Ferreira,Antony J Cutler,Helen Schuilenburg,Chris Wallace,Neil M Walker,Xaquin Castro Dopico,Henry Z Simons,David B Dunger,Whitney S Thompson,John A Todd,Linda S Wicker,Marcin L Pekalski,Deborah J Smyth,Meghavi Mashar

doi:10.1007/s00125-015-3509-8

Ricardo C Ferreira, Antony J Cutler + Show 12 more

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https://doi.org/10.1007/s00125-015-3509-8

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Abstract

Aims/hypothesisType 1 diabetes results from the autoimmune destruction of insulin-secreting pancreatic beta cells by T cells. Despite the established role of T cells in the pathogenesis of the disease, to date, with the exception of the identification of islet-specific T effector (Teff) cells, studies have mostly failed to identify reproducible alterations in the frequency or function of T cell subsets in peripheral blood from patients with type 1 diabetes.MethodsWe assessed the production of the proinflammatory cytokines IL-21, IFN-γ and IL-17 in peripheral blood mononuclear cells from 69 patients with type 1 diabetes and 61 healthy donors. In an additional cohort of 30 patients with type 1 diabetes and 32 healthy donors, we assessed the frequency of circulating T follicular helper (Tfh) cells in whole blood. IL-21 and IL-17 production was also measured in peripheral blood mononuclear cells (PBMCs) from a subset of 46 of the 62 donors immunophenotyped for Tfh.ResultsWe found a 21.9% (95% CI 5.8, 40.2; p = 3.9 × 10−3) higher frequency of IL-21+ CD45RA− memory CD4+ Teffs in patients with type 1 diabetes (geometric mean 5.92% [95% CI 5.44, 6.44]) compared with healthy donors (geometric mean 4.88% [95% CI 4.33, 5.50]). Consistent with this finding, we found a 14.9% increase in circulating Tfh cells in the patients (95% CI 2.9, 26.9; p = 0.016).Conclusions/interpretationThese results indicate that increased IL-21 production is likely to be an aetiological factor in the pathogenesis of type 1 diabetes that could be considered as a potential therapeutic target.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3509-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Highlights

Type 1 diabetes is a T cell mediated autoimmune disease characterised by exogenous insulin dependency resulting from the destruction of the insulin-producing beta cells
To avoid increased variability caused by CD4+ T cell subset heterogeneity and intra-individual variation in the composition of the immune subsets, we have normalised our data on the memory CD45RA− CD4+ T effector (Teff) population for IL-21 and IFN-γ and the CCR6+ subset of this same memory population for IL-17, a chemokine receptor expressed ubiquitously on Th17 cells [13] (Fig. 1a)
We found that the frequency of IL-21+ cells within the memory CD45RA− Teff cell population was increased in type 1 diabetes patients compared with healthy donors

Summary

Introduction

Type 1 diabetes is a T cell mediated autoimmune disease characterised by exogenous insulin dependency resulting from the destruction of the insulin-producing beta cells. There is evidence from mouse models for a role of the IL-21 pathway in type 1 diabetes [9], but aside from the established IL2-IL21 region association with type 1 diabetes risk [10], we have only identified one published, recent study that reported increased frequencies of circulating CD4+ T follicular helper (Tfh) cells together with enhanced expression of IL-21 in type 1 diabetes patients [8]. This contrasts with several reports of increases in Tfh frequencies in other autoimmune diseases such as Sjogren’s syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis, autoimmune thyroid disease, juvenile dermatomyositis and multiple sclerosis [11]

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