IL-21 Promotes Lupus-like Disease in Chronic Graft-versus-Host Disease through Both CD4 T Cell- and B Cell-Intrinsic Mechanisms

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2012; 189(2):1081-93. DOI: 10.4049/jimmunol.1200318
Source: PubMed


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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    • "IL-21 was also initially proposed as an important T cell-derived soluble factor regulating TFH differentiation through engagement of the IL-21R on recently activated CD4+ T cells prior to lineage commitment [8], [11], [13]. Subsequent reports [12], [32] including our findings herein demonstrating a reduced (by ∼ 50%) TFH response in the dLN of IAV-infected il-21rα−/− mice (Fig. 1b) further substantiates the contribution of IL21 to TFH differentiation. However, it was unclear whether IL-21 acts directly on naïve/recently activated CD4+ T cells to drive TFH differentiation [4], [6], [12]. "
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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 · 3.23 Impact Factor
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    • "Further study showed that treatment with an IL-21-neutralizing antibody once per week for 4 weeks could inhibit the expansion of Tfh cells in spleens and reduce the titers of ANA, ds-DNA and renal scores of MRL/lpr mice (Figure S2). These data indicated that IL-21 is a promoting factor in the differentiation/expansion of Tfh cells, germinal center formation, antibody production, and autoimmunity in murine model of lupus [29], [30], [31]. "
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    PLoS ONE 05/2013; 8(4):e62855. DOI:10.1371/journal.pone.0062855 · 3.23 Impact Factor
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