Session Type: Abstract Submissions (ACR)
We have previously shown that IL-21 promotes autoimmunity in a mouse model of lupus through both CD4 and B cell intrinsic mechanisms. Recent studies have shown increased expression of IL-21 in CD4 cells from lupus patients and a strong association between genetic polymorphisms in IL-21 and IL-21R and systemic lupus erythematosus. While these data suggest that IL-21 blockade may be an attractive therapeutic option in SLE, factors responsible for IL-21 upregulation and the effects of IL-21/IL-21R interaction on T and B cell subsets in lupus patients have not been fully characterized. To this end we assessed the expression of IL-21 in response to cytokines, the expression of IL-21R on CD4 cells and B cells from lupus patients compared to controls and the effect of IL-21/IL-21R interaction on these cells.
IL-21, IL-17, IFNg levels and IL-21R expression were determined in CD4, CD8 T cells and B cells by immunostaining. The proliferative response of purified CD4 cells and B cells to IL-21 was determined by [3H] -Thymidine incorporation. IL-21R binding ability using biotinylated IL-21, IL-21 induced STAT-3 phosphorylation, plasma cell differentiation, IgG and IL-10 production by lupus and control B cells were determined by immunostaining and ELISA, respectively.
IL-21 expression was significantly increased in PMA/ionomycin stimulated CD4 and CD8 T cells from lupus patients compared to controls. Functionally, supernatants of TCR stimulated CD4 cells from lupus patients induced higher levels of STAT-3 phosphorylation (which was inhibited by IL-21R:Fc) in normal B cells compared to supernatants from controls. The expression of IL-21 in TCR stimulated lupus CD4 T cells was upregulated by agonistic ICOS ligation and IL-12 but not by IFNa, IL-6, IL-10, IL-27 or TNFa. Consistent with IL-12 mediated upregulation, a higher proportion of IL-21 positive CD4 cells coexpressed IFNg (20±4%) compared to IL-17 (7±3%). IL-21 expression correlated with IL-17 expression in unstimulated and TCR stimulated CD4 T cells from lupus patients and IL-21 increased the proportion of IL-17+ CD4 T cells. IL-21R was detected at low levels on unstimulated naïve and memory CD4 T cells from both lupus patients and controls and was upregulated to a similar degree by T cell stimulation. However, CD4 T cells from patients and controls displayed decreased susceptibility to IL-21 proliferative effects. B cells from lupus patients expressed significantly higher IL-21R expression at baseline compared to controls. Among B cells CD27+CD38+plasmablasts and CD27+CD38- memory B cells from lupus patients but not CD27-CD38- naïve cells had higher binding ability for IL-21 compared to normal controls. IL-21 induced significantly higher STAT-3 phosphorylation and proliferation but not IgG and IL-10 production in lupus B cells.
IL-12 and ICOS ligation upregulate the expression of IL-21 in CD4 T cells from lupus patients. IL-21R expression and responsiveness to IL-21 is higher in B cells than CD4 cells from lupus patients, especially in plasmablasts and memory B cells. Therefore IL-21 blockade may attenuate IL-21 dependent aspects of B cell hyperactivity to a larger extent than CD4 T cell abnormalities such as expansion of Th17 cells.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-21il-21r-interaction-on-lymphocyte-subsets-from-lupus-patients/