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Regulation of IFN- Production by B Effector 1 Cells: Essential Roles for T-bet and the IFN- Receptor¹

David P. Harris^*, Stephen Goodrich^*, Andrea J. Gerth, Stanford L. Peng and Frances E. Lund^2,*

^* Trudeau Institute, Saranac Lake, NY 12983; and Department of Internal Medicine/Rheumatology, Washington University School of Medicine, St. Louis, MO 63105

This manuscript systematically identifies the molecular mechanisms that regulate the ability of B cells to produce the critical type 1 cytokine, IFN-. B cells produce IFN- in response to IL-12 and IL-18 and when primed by Th1 cells. We show that development of IFN--producing B cells by either Th1 cells or IL-12/IL-18 is absolutely dependent on expression of the IFN-R and the T-box transcription factor, T-bet. Interestingly, although T-bet up-regulation in developing B effector 1 (Be1) cells is controlled by IFN-R-mediated signals, STAT1-deficient B cells up-regulate T-bet and produce IFN-, indicating that additional transcriptional activators must be coupled to the IFN-R in B cells. Finally, we show that although IL-12/IL-18 or IFN--producing Th1 cells are required to initiate transcription of the IFN- gene in B cells, sustained expression of IFN- and T-bet by B cells is dependent on an IFN-/IFN-R/T-bet autocrine feedback loop. These findings have significant implications, because they suggest that IFN--producing B cells not only amplify Th1 responses, but also imprint a type 1 phenotype on B cells themselves. In the case of immune responses to bacterial or viral pathogens, this B cell-driven autocrine feedback loop is likely to be beneficial; however, in the case of B cell responses to autoantigens, it may result in amplification of the autoimmune loop and increased pathology.

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