Manuscript # JVI00063-13, Edited version IL-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells

Abstract Long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunit y. The generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific CD4 T cells and B cells and the formation of germinal centers (GCs). In this study, we have examined the role of the cytokine IL -21 in regulating humoral immunity during acute viral infections. Using IL -21 receptor deficient (IL-21R -/- ) mice we found that virus -specific CD4 T cells were generated after infection with LCMV and that these CD4 T cells differentiated into T follicular helper (T FH )-like cells in the absence of IL-21 signaling. There was also no defect in the formation of GCs although after day 15 these GCs disappeared faster in IL-21R -/- mice compared to wild -type mice. Isotype switching and the initial LCMV -specific IgG response was normal in IL-21R -/- mice. However, these mice exhibited a profound defect in generating long -lived plasma cells and in sustaining antibody levels over time. Similar results were seen after infection of IL-21R