Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States
John E Bradley
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
Wojciech Wojciechowski
Center for Pediatric Biomedical Research, Flow Cytometry Shared Resource Laboratory, University of Rochester School of Medicine and Dentistry, Rochester, United States
Travis Ptacek
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States; Informatics Group, Center for Clinical and Translational Science, The University of Alabama at Birmingham, Birmingham, United States
Maria I Danila
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
Jeffrey C Edberg
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
S Louis Bridges Jr
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
Robert P Kimberly
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
W Winn Chatham
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, United States
Trenton R Schoeb
Department of Genetics, Animal Resources Program, The University of Alabama at Birmingham, Birmingham, United States
Alexander F Rosenberg
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, United States; The Informatics Institute, The University of Alabama at Birmingham, Birmingham, United States
Jeremy M Boss
Department of Microbiology and Immunology, Division of Rheumatology, Emory University, Atlanta, United States
Ignacio Sanz
Department of Medicine, Division of Rheumatology, Emory University, Atlanta, United States
Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ 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 IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.
