IL-21 is necessary to both induce and sustain humoral immunity to Plasmodium

Abstract

Abstract Resistance to malaria depends on the generation of antibodies derived from germinal center (GC) responses. T follicular helper (Tfh) cells play a critical role in the selection of high-affinity GC B cells that can differentiate into either memory B cells or antibody secreting plasma cells. Mice deficient in IL-21 or its receptor fail to mount GC responses, secrete parasite-specific IgG and control primary Plasmodium infections. However, whether IL-21 exerts temporally distinct contributions to either the maintenance of GC reactions or memory, during primary anti-Plasmodium humoral immunity or memory recall responses, is not known. We hypothesize that CD4+ T cell derived IL-21 acts to support the maintenance of GC B cells and is critical for secondary humoral immune reactions orchestrated by memory Tfh. To test this hypothesis, we utilized IL-21-VFP reporters and developed cell type-specific and conditional IL-21 knockout systems. Our data show that Tfh-derived IL-21 expression peaks during the first week of infection as GC are initially forming. Following tamoxifen mediated deletion of CD4 derived IL-21 during an established GC reaction (days 16–18 p.i.), we observed significant reductions in GC B cells and loss of memory B cell-derived, parasite-specific IgG production following challenge. Thus, in addition to inducing GC responses, our experiments show that IL-21 is critical for sustaining GC responses and the formation of functional memory B cell responses.