IL-21 Promotes CD4 T Cell Responses by Phosphatidylinositol 3-Kinase-Dependent Upregulation of CD86 on B Cells.

The cytokine IL-21 is a potent immune modulator with diverse mechanisms of action on multiple cell types. IL-21 is in clinical use to promote tumor rejection and is an emerging target for neutralization in the setting of autoimmunity. Despite its clinical potential, the biological actions of IL-21 are not yet fully understood and the full range of effects of this pleiotropic cytokine are still being uncovered. In this study, we identify a novel role for IL-21 as an inducer of the costimulatory ligand CD86 on B lymphocytes. CD86 provides critical signals through T cell-expressed CD28 that promote T cell activation in response to Ag engagement. Expression levels of CD86 are tightly regulated in vivo, being actively decreased by regulatory T cells and increased in response to pathogen-derived signals. In this study, we demonstrate that IL-21 can trigger potent and sustained CD86 upregulation through a STAT3 and PI3K-dependent mechanism. We show that elevated CD86 expression has functional consequences for the magnitude of CD4 T cell responses both in vitro and in vivo. These data pinpoint CD86 upregulation as an additional mechanism by which IL-21 can elicit immunomodulatory effects

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

This is the final published version. It first appeared at http://link.springer.com/article/10.1007%2Fs00125-015-3509-8.Aims/hypothesis\ud \ud Type 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.\ud Methods\ud \ud We assessed the production of the proinflammatory cytokines IL-21, IFN-? 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.\ud Results\ud \ud We 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).\ud Conclusions/interpretation\ud \ud These 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.This work was supported by the JDRF UK Centre for\ud Diabetes - Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003) in collaboration with M. Peakman and T. Tree at King?s College\ud London, the JDRF, the Wellcome Trust (WT; WT061858/091157 and\ud 083650/Z/07/Z) and the National Institute for Health Research\ud Cambridge Biomedical Research Centre (CBRC). The Cambridge\ud Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust\ud Strategic Award (100140). RCF is funded by a JDRF post-doctoral fellowship\ud (3-2011-374). CW is funded by the Wellcome Trust (088998).\ud The funding organisations had no involvement with the design and\ud conduct of the study; collection,management, analysis, and interpretation\ud of the data; and preparation, review, or approval of the manuscript