IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation

Zumaquero, E.; Stone, S. L.; Scharer, C. D.; Jenks, S. A.; Nellore, A.; Mousseau, B.; Rosal-Vela, A.; Botta, D.; Bradley, J. E.; Wojciechowski, W.; Ptacek, T.; Danila, M. I.; Edberg, J. C.; Bridges, S. L.; Kimberly, R. P.; Chatham, W. W.; Schoeb, T. R.; Rosenberg, A.; Boss, J. M.; Sanz, I.; Lund, F. E.

doi:10.1101/557520

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bioRxiv · 10.1101/557520

IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation

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Abstract

Although B cells expressing the IFN{gamma}R or the IFN{gamma}-inducible transcription factor T-bet drive autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFN{gamma} signaling in human antibody responses is unknown. We show that elevated levels of IFN{gamma} in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naive B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFN{gamma}, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFN{gamma} or IFN{gamma}-producing T cells. IFN{gamma} promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFN{gamma} signals poise B cells to differentiate by increasing their responsiveness to IL-21.

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Zumaquero, E., Stone, S. L., Scharer, C. D., Jenks, S. A., Nellore, A., Mousseau, B., Rosal-Vela, A., Botta, D., Bradley, J. E., Wojciechowski, W., Ptacek, T., Danila, M. I., Edberg, J. C., Bridges, S. L., Kimberly, R. P., Chatham, W. W., Schoeb, T. R., Rosenberg, A., Boss, J. M., Sanz, I., Lund, F. E.. 2019-02-21. IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation. https://doi.org/10.1101/557520

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