Differentiation of B cells to long-lived memory B cells and affinity matured- antibody secreting B cells is a critical event of the humoural immune system. These qualities of a B cell are determined primarily in lymphoid structures called the Germinal Centres (GC). Given the importance of antibodies in conferring host protection against infections as well as in regulating autoimmunity, identification of molecules that control B cell differentiation is essential. IL-27, an heterodimeric cytokine, has been associated with several infectious and autoimmune disorders in humans. Mouse studies have highlighted a critical role for IL-27 in driving GC-responses via enhancing T follicular helper cell activity, however, how this cytokine influences B cell differentiation during a GC response is poorly characterized. We have investigated the effect of hIL-27 on purified human naïve, memory and GC-B cells in-vitro across several time-points of differentiation. We show that IL-27 promotes phenotypic features of GC B cells and induces a strong upregulation in Fas expression on these cells. Mouse bone-marrow chimera experiments confirmed that the absence of IL-27 signaling resulted in B cell intrinsic defects in GC responses. These defects were associated with an altered isotype switching of B cells and consequently, different constitution of immune complexes in the kidneys of lupus-prone Sanroque mice. Altogether, our data suggest an important role for IL-27 signaling in the B cell differentiation process, and the regulation of lupus.