B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1.

A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4(+) T cells into T follicular helper cells (T(FH) cells) during an immune response. T(FH) cells collaborate with B cells in the formation of germinal centers (GCs) during T cell-dependent antibody responses, in part through secretion of critical cytokines such as IL-21. In this study, we demonstrate that loss of either IL-6 or IL-21 has marginal effects on the generation of T(FH) cells and on the formation of GCs during the response to acute viral infection. However, mice lacking both IL-6 and IL-21 were unable to generate a robust T(FH) cell-dependent immune response. We found that IL-6 production in follicular B cells in the draining lymph node was an important early event during the antiviral response and that B cell-derived IL-6 was necessary and sufficient to induce IL-21 from CD4(+) T cells in vitro and to support T(FH) cell development in vivo. Finally, the transcriptional activator Oct2 and its cofactor OBF-1 were identified as regulators of Il6 expression in B cells.