During a T dependent (T-D) response, activated B cells undergo a number of critical events to establish a robust antibody response and long-lived memory. These regulated events include migration, T and B cell interaction, proliferation, selection and differentiation. IL-21 is the signature cytokine produce by T follicular helper cells. Initial studies have shown IL-21 to be a complex regulator of immune response with the capacity to upregulate the transcription factors Bcl-6 and Blimp-1 in vitro. Subsequent studies have established IL-21 acts directly on B cells to regulate several aspects of the immune response including germinal center (GC) maintenance and the production of plasma cells and memory cells both before and after GC formation. The proliferative defect in GC B cells has been confirmed by the use of the transgenic mouse Fucci/IL-21 receptor-/-.
Exactly how IL-21 mediates these affects prior to GC formation are not clear. Using an SwHEL/IL-21 receptor-/- mouse model in adoptive transfer experiments, we have found the initial proliferation of KO B cells to be unaffected. However, there is significant reduction in the frequency and numbers of KO B cells from the time point of nascent GC establishment. Although KO B cells can display a GC B cell phenotype (CD38lo, IgD-, GL7+ FAS+), the proportion that upregulated Bcl6, the transcription factor required for GC B cell differentiation, is significantly lower than that of WT across all time points analysed. Conversely, the proportion of KO B cells with a memory phenotype was significantly increased, even prior to GC formation. Preliminary histological data using immunoflourecence showed the KO B cells to be mislocalised before and after GC establishment, suggesting a possible basis for the GC deficiency. These data highlight novel roles for IL-21 in the early phases of T-D B cell responses.