IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and B cell-intrinsic mechanisms.
ABSTRACT T cell-driven B cell hyperactivity plays an essential role in driving autoimmune disease development in systemic lupus erythematosus. IL-21 is a member of the type I cytokine family with pleiotropic activities. It regulates B cell differentiation and function, promotes T follicular helper (T(FH)) cell and Th17 cell differentiation, and downregulates the induction of T regulatory cells. Although IL-21 has been implicated in systemic lupus erythematosus, the relative importance of IL-21R signaling in CD4(+) T cells versus B cells is not clear. To address this question, we took advantage of two induced models of lupus-like chronic graft-versus-host disease by using wild-type or IL-21R(-/-) mice as donors in the parent-into-F1 model and as hosts in the Bm12→B6 model. We show that IL-21R expression on donor CD4(+) T cells is essential for sustaining T(FH) cell number and subsequent help for B cells, resulting in autoantibody production and more severe lupus-like renal disease, but it does not alter the balance of Th17 cells and regulatory T cells. In contrast, IL-21R signaling on B cells is critical for the induction and maintenance of germinal centers, plasma cell differentiation, autoantibody production, and the development of renal disease. These results demonstrate that IL-21 promotes autoimmunity in chronic graft-versus-host disease through both CD4(+) T cell- and B cell-intrinsic mechanisms and suggest that IL-21 blockade may attenuate B cell hyperactivity, as well as the aberrant T(FH) cell pathway that contributes to lupus pathogenesis.
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ABSTRACT: IL-21 is a type-I cytokine that has pleiotropic immuno-modulatory effects. Primarily produced by activated T cells including NKT and TFH cells, IL-21 plays a pivotal role in promoting TFH differentiation through poorly understood cellular and molecular mechanisms. Here, employing a mouse model of influenza A virus (IAV) infection, we demonstrate that IL-21, initially produced by NKT cells, promotes TFH differentiation by promoting the migration of late activator antigen presenting cell (LAPC), a recently identified TFH inducer, from the infected lungs into the draining lymph nodes (dLN). LAPC migration from IAV-infected lung into the dLN is CXCR3-CXCL9 dependent. IL-21-induced TNF-α production by conventional T cells is critical to stimulate CXCL9 expression by DCs in the dLN, which supports LAPC migration into the dLN and ultimately facilitates TFH differentiation. Our results reveal a previously unappreciated mechanism for IL-21 modulation of TFH responses during respiratory virus infection.PLoS ONE 09/2014; 9(9):e105872. DOI:10.1371/journal.pone.0105872 · 3.53 Impact Factor
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ABSTRACT: Background Autoimmune responses mediated by CD4+ T cells may contribute to the development of chronic obstructive pulmonary disease (COPD). However, little is known about the frequency of peripheral blood Th17 cells and Tregs in Chinese patients with COPD. This study is aimed at determining the frequency of circulating Th17 and Tregs in patients with moderate and severe COPD, heavy smokers, and healthy controls (HC).Method The percentages of circulating Th17 cells and Tregs were determined by flow cytometry in 32 patients with moderate COPD, 33 patients with severe COPD, 35 smokers, and 31 HC. The concentrations of serum Th17- and Treg-related cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The levels of retinoic acid orphan receptor (ROR)-γt and Forkhead box (Fox) p3 mRNA transcripts in peripheral blood mononuclear cells were determined by real-time PCR. The potential correlation between the percentages of Th17 Tregs, serum cytokines and lung function was evaluated.ResultsIn comparison with that in the smokers and HC, significantly higher frequencies of Th17 cells and higher levels of ROR-γt mRNA transcripts and serum IL-17A, IL-6, IL-21, IL-22 and IL-23, but lower frequency of Tregs and lower levels of Foxp3 and serum IL-10 were detected in patients with moderate and severe COPD. The increased ratios of Th17 to Tregs were negatively correlated with the values of FVC, FEV1, and FEV1/FVC.Conclusions An imbalance of circulating Th17 cells and Tregs is associated with the deterioration of pulmonary function in patients with moderate and severe COPD.The Clinical Respiratory Journal 04/2014; DOI:10.1111/crj.12147 · 2.20 Impact Factor
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ABSTRACT: Induced mouse models of systemic lupus erythematosus (SLE) have been developed to complement the spontaneous models. This chapter describes the methods used in the pristane-induced model and the chronic graft-versus-host disease (cGVHD) model, both of which have been extensively used. We will also outline the specific mechanisms of systemic autoimmunity that can be best characterized using each of these models.Methods in molecular biology (Clifton, N.J.) 01/2014; 1134:103-30. DOI:10.1007/978-1-4939-0326-9_9 · 1.29 Impact Factor