Background/Purpose: IL-21 is a member of the type I cytokine family with pleiotropic activities. IL-21 enhances CD8 T cells maturation into cytotoxic T lymphocytes (CTL), promotes the differentiation of T follicular helper (T_FH)  and Th17 cells while downregulating Tregulatory (Treg) cells and regulates B-cell proliferation and survival, Ig production and class switching. In humans, an association of IL-21 and IL-21R polymorphisms with SLE were reported, while studies in murine models of lupus have indicated that IL-21 blockade was beneficial in MRL-Fas^lpr, BXSB-Yaa and chronic graft versus host disease (cGVHD) mice.  Furthermore, we have shown that in the cGVHD model, IL-21 promotes the autoimmune phenotype by both B and CD4 T cell intrinsic mechanisms. The relative importance of IL-21R signaling in CD8 T cells on autoimmune parameters in murine lupus has not yet been assessed. In this study we set to determine whether the effect of IL-21 in promoting CD8 T cell differentiation into CTL, leads to the elimination of autoreactive B cells and subsequently the attenuation of autoimmune parameters in murine lupus.

Methods: To address this question we have used two established models of chronic and acute GVHD to dissect the effect on autoimmune parameters of IL-21R signaling in donor CD8 T cells. Specifically, IL-21R sufficient and deficient mice were used as donors in the B6-into-F1 model of acute (a)GVHD. In addition, the effect of exogenous IL-21 on autoimmune parameters was assessed in the DBA-into-F1 lupus-like model of cGVHD that is characterized by defective CTL activity resulting in the persistence of autoreactive B cells. In both models, parameters of acute and cGVHD including donor CD4 and CD8 T cell engraftment, host B cell number and activation, anti-ssDNA autoAb production, in vivo donor anti-host CTL activity were assessed at two weeks after disease induction.

Results: Acute GVHD induced by injection of IL-21R^-/-splenocytes on the B6 background into B6D2F1 hosts, resulted in the conversion of acute to chronic GVHD phenotype, as demonstrated by increased autoAb production, decreased host B cell elimination (57%±6 vs. 90%±0.3; p=0.03) and impaired in vivo CTL activity along with significant decrease in donor (d)CD4 and dCD8 cell expansion. In contrast, DBA-into-F1 cGVHD mice that received rmIL-21 exhibited attenuated autoimmune parameters with respect to host B cell expansion and activation, anti-ssDNA autoAb production along with enhanced donor CD8 expansion and donor anti-host CTL activity. In both models, IL-21/IL-21R interaction on donor CD8 cells resulted in their increased proliferation, expansion and differentiation into CTLs that expressed higher levels of granzyme B and IFNg levels, but nor perforin.

Conclusion: These results suggest that lack of IL-21/IL-21R interaction on CD8 T cells converts acute to chronic GVHD by impairing B cell elimination, while in cGVHD, IL-21 administration attenuates the humoral component by enhancing CTL generation and subsequently host B cells elimination. Therefore, IL-21R signaling on CD8 T cells attenuates disease phenotype in murine lupus, thus opposing the enhancing effects of IL-21R signaling on CD4 T cells and B cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ctl-promoting-effects-of-il-21-results-in-b-cell-elimination-and-disease-improvement-in-a-murine-model-of-lupus/