%0 Journal Article 
%A Zumaquero, Esther
%A Stone, Sara L
%A Scharer, Christopher D
%A Jenks, Scott A
%A Nellore, Anoma
%A Mousseau, Betty
%A Rosal Vela, Antonio
%A Botta, Davide
%A Bradley, John E
%A Wojciechowski, Wojciech
%A Ptacek, Travis
%A Danila, Maria I
%A Edberg, Jeffrey C
%A Bridges, S Louis
%A Kimberly, Robert P
%A Chatham, W Winn
%A Schoeb, Trenton R
%A Rosenberg, Alexander F
%A Boss, Jeremy M
%A Sanz, Ignacio
%A Lund, Frances E
%T IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation
%D 2019
%@ 2050-084X
%U http://hdl.handle.net/10498/35094
%X Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet
promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for
IFNg signaling in human antibody responses is unknown. We show that elevated levels of IFNg in
SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg
(DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naı¨ve B cells form T-bethi
pre-ASCs following stimulation with either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand
and that IL-21 dependent ASC formation is significantly enhanced by IFNg or IFNg-producing T
cells. IFNg 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 IFNg signals poise B cells to differentiate by increasing their
responsiveness to IL-21
%~ Universidad de Cádiz