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

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 wit...

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Bibliographic Details
Published ineLife Vol. 8
Main Authors Zumaquero, Esther, Stone, Sara L, Scharer, Christopher D, Jenks, Scott A, Nellore, Anoma, Mousseau, Betty, Rosal-Vela, Antonio, Botta, Davide, Bradley, John E, Wojciechowski, Wojciech, Ptacek, Travis, Danila, Maria I, Edberg, Jeffrey C, Bridges, Jr, S Louis, Kimberly, Robert P, Chatham, W Winn, Schoeb, Trenton R, Rosenberg, Alexander F, Boss, Jeremy M, Sanz, Ignacio, Lund, Frances E
Format Journal Article
LanguageEnglish
Published England 15.05.2019
Subjects
B-Lymphocyte Subsets - chemistry
B-Lymphocyte Subsets - drug effects
B-Lymphocyte Subsets - physiology
Cell Differentiation
Epigenesis, Genetic
Gene Regulatory Networks
Humans
Interferon-gamma - metabolism
Interleukins - metabolism
Lupus Erythematosus, Systemic - pathology
T-Box Domain Proteins - analysis
Toll-Like Receptor 7 - metabolism
Toll-Like Receptor 8 - metabolism
mouse
systemic lupus erythematosus
interferons
B lymphocytes
inflammation
antibody secreting cells
T-bet
human
immunology
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Summary: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 IgD CD27 CD11c CXCR5 (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet 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 and loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.
ISSN:2050-084X