IL-21 Exacerbates Autoimmune Myositis by Enhancing the Accumulation of GM-CSF–Producing γδ T Cells in the Muscle

Abstract

IL-21 is suggested to be involved in the development of some autoimmune diseases; however, the role of IL-21 in autoimmune inflammatory myopathies (IMs) remains unknown. In this study, we found that serum levels of IL-21 were significantly elevated in a subset of IM patients. Upon the induction of experimental autoimmune myositis (EAM), IL-21 was produced by CD4+ T cells in the muscle, and muscle weakness and muscle inflammation were less obvious in IL-21–deficient (IL-21−/−) mice compared with those in wild-type (WT) mice. Analysis of inflammatory cytokine production from draining lymph node cells of EAM-induced mice revealed that GM-CSF production was significantly decreased in IL-21−/− mice. Importantly, GM-CSF production from γδT cells, but not CD4+ T cells, was significantly reduced in EAM-induced IL-21−/− mice. In addition, the severity of EAM was attenuated by GM-CSF neutralization in WT mice or γδT cell deficiency. The majority of muscle-infiltrating GM-CSF–producing γδT cells expressed Vγ4+Vδ4+ TCR, and the number of Vγ4+Vδ4+ cells in the muscle was significantly decreased in EAM-induced IL-21−/− mice as compared with that in EAM-induced WT mice. Moreover, muscle-infiltrating Vγ4+Vδ4+ cells exhibited CX3CR1high phenotype, and the induction of Cx3cl1, a ligand for CX3CR1, in the muscle was reduced in EAM-induced IL-21−/− mice. Furthermore, reporter assays revealed that IL-21 activated the promoter of Cx3cl1. Consistent with these findings, serum levels of CX3CL1 were correlated with the levels of IL-21 in IM patients. Taken together, these results suggest that IL-21 facilitates autoimmune myositis through the accumulation of GM-CSF–producing Vγ4+Vδ4+ cells in the muscle possibly via CX3CR1-CX3CL1 pathways.