IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21-producing B helper CD8+ T cells.

IL-6 is known to contribute to the differentiation of CD4 T cells into different subsets of effector T helper cells. Less is known about the potential of IL-6 in regulating CD8 T cell effector function. Here, we identify IL-6 as a master regulator of IL-21 in effector CD8 T cells. IL-6 promotes the differentiation of a subset of naive CD8 T cells that express IL-6R into a unique population of effector CD8 T cells characterized by the production of high levels of IL-21 and low levels of IFN-γ. Similar to CD4 T follicular helper (Tfh) cells, IL-21-producing CD8 T cells generated in the presence of IL-6 directly provide help to B cells to induce isotype switching. CD8 T cell-derived IL-21 contributes to the production of protective virus-specific IgG antibodies during influenza virus infection. Thus, this study reveals the presence of a new mechanism by which IL-6 regulates antibody production during viral infection, and a novel function of effector CD8 T cells in the protection against viruses.