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Abstract
Cytokines are an essential component of both normal and aberrant immune responses, such as in autoimmune disease. Interleukin (IL)-21 is a member of the common gamma chain family of cytokines and is adjacent to IL-2 within the strongest non-MHC-linked locus for type-1 diabetes (T1D) susceptibility in non-obese diabetic (NOD) mice. Recent studies demonstrate that IL-21 is necessary for the development of autoimmune disease in several models including T1D in NOD mice. This study explores the critical role of IL-21 in the pathogenesis of T1D. In this study, we demonstrate that the amount of IL-21, but not IL-2, correlated with T1D incidence. Whilst IL-21 is found in high expressing and low expressing allelic forms, IL-2 appears to be kept at a similar level between mouse strains due to differences in mRNA stability. IL-21 is produced in abundance within the autoimmune lesions of the NOD mouse by a novel CD4+ T helper (Th) subset, marked by co-expression of the gut-homing chemokine receptor CCR9. Whilst these CCR9+ IL-21-producing Th cells could be found in healthy mice and humans, they were concentrated in the inflamed pancreas. Critically, the ultimate target of IL-21 is CD8+ T cells whose receptiveness to IL-21 is necessary for the development of diabetes. We also demonstrate successful intervention at a late preclinical stage through neutralisation of IL-21 with IL-21R/Fc. Indeed, when combined with islet allograft transplantation, this therapeutic approach could cure diabetes. We found that the influence of IL-21 on a graft-mounted immune response was robust, as absence of IL-21 signalling was also found to prevent islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with T1D.