IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T_FH) cells. T^FH cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T^FH cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of TFH cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4⁺ T cells and the expression of T^FH cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T^FH cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra^-/- mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.