IL-21 Promotes Intestinal Memory IgA Responses

The role of IL-21, produced mainly by Th17 cells and T follicular helper cells, has been intensively investigated in B cell differentiation and Ab class switch. However, how IL-21 regulates memory IgA⁺ B cell development and memory IgA responses in the intestines is still not completely understood. In this study, we found the total IgA⁺ B cells as well as CD38⁺CD138^-IgA⁺ memory B cells were significantly increased in intestinal lamina propria (LP) of TCRβxδ^-/- mice after transfer of microbiota Ag-specific Th17 cells but not Th1 cells. Although IL-21R^-/- mice or IL-17R^-/- mice showed decreased Ag-specific memory IgA production in the intestines upon Infection with Citrobacter rodentium, the percentage of IgA⁺CD38⁺CD138^- memory B cells in Peyer's patches and LP was decreased only in IL-21R^-/- mice, but not in IL-17R^-/- mice, after reinfection with C. rodentium compared with wild-type mice. Blockade IL-21 in vivo suppressed intestinal C. rodentium-specific IgA production as well as IgA⁺CD38⁺CD138^- memory B cells in Peyer's patches and LP. Furthermore, IL-21 significantly induced B cell IgA production in vitro, with the increased expression of genes related with class-switching and memory B cell development, including Aicda, Ski, BMI1, and Klf2. Consistently, Aicda and Ski expression was decreased in B cells of IL-21R^-/- mice after C. rodentium reinfection. In conclusion, our study demonstrated that IL-21 promotes intestinal memory IgA B cell development, possibly through upregulating differentiation-related and class switching-related genes, indicating a potential role of IL-21 in memory IgA⁺ B cell responses in the intestines.