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

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.

CD4 T cell differentiation in type 1 diabetes

“…Consistent with this, an increase in peripheral blood T cells with a Tfh phenotype, has also been reported in two independent cohorts of T1D patients, one of which comprised exclusively new onset patients (within 2 years' diagnosis, mean age 23) [107], while the other included individuals with disease duration ranging from 2 to 20 years (median age 32) [67]. Thus, in both mouse models and in humans, an expansion of cells with a Tfh phenotype appears to be a feature of autoimmune diabetes ( [67,106], providing strong support for such a notion. However, as IL-21 can also be produced by other T cells, including Th17 cells [81,82], and immunosuppressive Tr1 cells [110], the contribution of non-Tfh populations cannot be excluded.…”

“…Careful analysis of T cell cytokine production and chemokine receptor profiles established that the pancreatic lymph nodes of type 1 diabetic subjects had a higher frequency of Th17 cells [66]. More recently, an increase in the frequency of IL-17 1 cells was found in the peripheral blood of adult T1D patients when gating on CD45RA -CCR6 1 population of CD4 T cells [67]. Thus, several lines of evidence point to an increase in IL-17 production in the T1D setting.…”

“…In mice, early work implicated IL-17 in the pathogenic [106]. IL-21-producing T cells are elevated in T1D patients [67,106], and can co-express TNF-a and IFN-g [106].…”

“…It has been found recently that CD4 T cells from T1D patients produce higher levels of IL-21 in response to invitro restimulation than T cells from non-diabetic individuals [67,106]. Work by Kenefeck et al [106] focused on adult patients, with a mean age of 37, while analysis by Ferreira and colleagues [67] also included children (median age 14, range 6-42 years).…”

“…Work by Kenefeck et al [106] focused on adult patients, with a mean age of 37, while analysis by Ferreira and colleagues [67] also included children (median age 14, range 6-42 years). Importantly, both studies normalized their analysis to the memory cell population to avoid variation in the frequency of memory T cells affecting their results.…”