207: IL-27 signals to both B and T cells support germinal center function and the development of GC-driven lupus
IL-27 is a heterodimeric cytokine that shares sequence and structural homology with IL-12, IL-6 and IL-23. The bulk of the previous studies into IL-27 function have centered on its important role in directing CD4+T helper cell differentiation. The majority of in vivo models of inflammatory/autoimmune diseases and infection have indicated an immunosuppressive role for IL-27, through induction of IL-10 as well as direct suppression of TH17 and TH2 differentiation. For example, in models of T cell driven autoimmune disease, such as EAE, IL-27 suppresses the autoimmune response. However, our recent studies showed a surprisingly important pro-inflammatory role for IL-27 during germinal center responses. This effect was due, at least in part, to influences on T Follicular Helper (TFH) cell defects. We sought to investigate the effect of IL-27 signaling in a TFH driven model of lupus, the Sanroque mouse strain, by crossing IL27ra deficient mice with Sanroque mice. Deletion of IL27Ra reduced TFH and GC B cell numbers and ameliorated some aspects of disease in this model. Bone marrow chimeric approaches indicated that IL-27 signals directly to B cells contribute to development of disease. Although both chains of the IL-27 receptor are expressed by B cells, its effect on these cells during the antibody response is poorly characterized. We found that IL-27 stimulation of purified B cells in vitro enhances expression of the transcription factor Bcl-6 and promotes phenotypic features of GC B cells. Together, our data suggest that IL-27 signals to B cells play an important role in cell fate (i.e. GC versus plasma cell) determination and that these B cell specific effects contribute to the GC defect observed in IL-27Ra deficient mice.