(b) Incidence of T1D in or NOD.and NOD.or NOD.recipients and T1D onset was monitored (c). activation of autoreactive CD8+ T cells but is usually dispensable for the activated cells to develop effector functions and cause disease. Hence, therapeutic targeting of IL-21 in T1D may inhibit activation of naive autoreactive CD8+ T cells, but may have to be combined with other strategies to inhibit already activated cells. locus encompasses a 650 kb region on chromosome 3 and contains genes encoding interleukin (IL)-2 and IL-21 1,2. In the NOD mouse, polymorphisms at the gene promoter and decreased transcription and stability of IL-2 mRNA are implicated in reduced IL-2 production, which has been correlated with reduced frequency and functions of CD4+CD25+ regulatory T cells (Tregs) 1,3,4. The ability of the C57BL/6-derived locus to protect NOD L-Valine mice from insulitis and diabetes has been correlated with reduced IL-21 mRNA and protein levels 1,5,6. The importance of IL-21 in T1D pathogenesis is usually demonstrated by the failure of NOD mice lacking IL-21 or IL-21 receptor alpha chain (IL-21R) to develop T1D 7C11. How IL-21 promotes pathogenesis of T1D is not yet clear. IL-21 is usually produced mainly by natural killer (NK) T cells and CD4+ T cells 12,13. All CD4+ T helper subsets can produce varying amounts of IL-21, depending on the context of stimulation and the cytokine milieu 14,15. IL-21 acts as an autocrine growth factor that shifts the balance away from Tregs towards T helper type 17 (Th17) lineage, promoting inflammation and immune response 16,17. In psoriasis and multiple sclerosis Th17 cells, driven partly by IL-21, play a significant role in promoting tissue damage 18C20. Early studies in NOD mice lacking IL-21R have also implicated IL-21 in T1D pathogenesis via Th17 cells 8,15. However, the role of Th17 cells in the pathogenesis of T1D remains controversial. In fact, Th17 cells produced in the gut have been shown to exert a protective effect in T1D 21C25. CD8+ T lymphocytes play a key role in the pathogenesis of autoimmune diseases by causing damage to target organs 26. Two recent studies have implicated IL-21 in T1D pathogenesis via promoting growth and survival of CD8+ Mouse monoclonal to PTH T cells 9,11. Studies around the role of IL-21 in viral infections showed that IL-21 signalling is usually indispensable for strong primary and secondary CD8+ T cell responses to chronic viral infections 27C31. These studies suggested that IL-21 may also be needed for the efficient activation of autoreactive CD8+ T cells. This L-Valine possibility is usually supported by our recent finding that IL-21, in synergy with IL-15, enables naive autoreactive CD8+ T cells to respond to poor TCR agonists and induce disease in an engineered model of T1D 32. In the present study, we have examined the role of IL-21 in activating autoreactive CD8+ T cells in the NOD mouse L-Valine expressing the transgenic 8.3 T cell receptor (TCR) 33. Our findings indicate that IL-21 is required for the initial activation of autoreactive CD8+ T cells, but is usually dispensable for sustaining their effector functions and their ability to induce disease. Materials and methods Mice NOD mice (NOD/ShiLtJ) and 8.3 TCR transgenic NOD mice [NOD.Cg-Tg(TcraTcrbNY8.3)1Pesa/DvsJ; for brevity, 8.3-NOD] were purchased from the Jackson Laboratory (Bar Harbor, ME, USA). loci and were selected for further breeding. The progeny of the 11th back-cross were intercrossed to generate NOD.gene protects female 8.3-NOD mice from T1D and insulitis The 8. 3-NOD mouse expresses a highly pathogenic, MHC class I-restricted, transgenic 8.3 TCR specific to a peptide derived from the IGRP206C214 33,36. In these mice, the 8.3 TCR transgenic CD8+ T cells (8.3 T cells) infiltrate pancreatic islets from 3 weeks of age 33. Female 8.3-NOD mice develop T1D at 2C3 months of age compared to 4C6 months required for overt diabetes in non-TCR transgenic NOD mice 37. Disease penetrance in our NOD colony is usually greater than 90% in 8.3-NOD females and about 50% in males (Fig. 1a,b). Genetic ablation of the gene abrogated completely T1D incidence in female and male 8.3-NOD mice (Fig. 1a). Strikingly, a partial reduction in IL-21 availability was sufficient to reduce T1D incidence by 50C60% in gene heterozygosity did not diminish T1D incidence in male 8.3-NOD mice (Fig. 1b). IL-21 deficiency completely prevented mononuclear cell infiltration of pancreatic islets in 8.3-NOD mice (Fig. 1d). These results show that this highly diabetogenic 8. 3 TCR transgenic CD8+ T cells require IL-21 to induce insulitis and cause diabetes, and L-Valine L-Valine that a partial reduction in IL-21 availability is sufficient to attenuate their pathogenic potential. Open in a separate windows Fig. 1 Interleukin (IL)-21 is required for the development of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice expressing the 8.3 transgenic T cell receptor (TCR). (a).
