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

Abstract

34Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet drive autoimmunity 35 in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNg signaling in human 36 antibody responses is unknown. We show that elevated levels of IFNg in SLE patients correlate with 37 expansion of the T-bet expressing IgD neg CD27 neg CD11c + CXCR5 neg (DN2) pre-antibody secreting cell 38 (pre-ASC) subset. We demonstrate that naïve B cells form T-bet hi pre-ASCs following stimulation with 39 either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is 40 significantly enhanced by IFNg or IFNg-producing T cells. IFNg promotes ASC development by 41 synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, 42 which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and 43 epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNg signals poise B cells to 44 differentiate by increasing their responsiveness to 45 46 50 adaptive arms of the immune system, which ultimately leads to loss of immune tolerance in B and T 51 lymphocytes and the production of autoantibodies (Abs) by Ab-secreting B cells (ASCs) (1). The hallmark 52 SLE autoAbs recognize nuclear proteins and nucleic acids (2), which are also ligands for TLR7 and TLR9 53 that are expressed by innate immune cells and B cells (3). SLE autoAbs bound to their autoAgs form 54 immune complexes, which are responsible for many of the clinical manifestations of SLE, particularly 55 those associated with organ damage (2). Consistent with the important role for B cells and ASCs in SLE 56 pathogenesis (4), the only new drug approved to treat SLE in decades, Belimumab, targets B cells. 58Inflammatory cytokines and chemokines also contribute to SLE pathogenesis (5). SLE patient PBMCs 59 often exhibit a type I interferon (IFN) transcriptional signature and systemic IFNa is elevated in many 60 patients (6). It is less well appreciated that IFNg is also increased in some SLE patients (7-9) and that a 61 distinct IFNg transcription signature can be detected in PBMCs from a portion of SLE patients (10, 11). 62Interestingly, elevated serum IFNg can be observed years before IFNa or autoAbs are detected in SLE 63 patients and much earlier than clinical disease (12, 13). Consistent with these observations, B cells from 64 SLE patients can exhibit signs of prior IFNg exposure. For example, CXCR3 and T-bet, two IFNg-inducible 65 proteins (14), are more highly expressed by circulating B cells from SLE patients compared to healthy 66 controls (8,(15)(16)(17)(18)(19). Moreover, data from mouse SLE models show that clinical disease is dependent on 67 B cell-specific expression of the IFNgR and the IFNg-induced transcription factors and T-68 bet in some (23, 24) but not all (21, 25) models. Taken together, these data suggest that IFNg-driven 69 inflammation may contribute to SLE B cell-driven pathophysiology. 71Two populations of...

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

“…The fraction of DN B cells lacking CXCR5 and CD21 (DN2 cells) is greatly expanded in patients with active SLE, and this expansion correlates with increased disease activity and poorer outcomes. We also showed that DN2 cells are induced through IFN-γ-IL-21 in a TLR7-dependent fashion 18 , correlate with IL-6 and IP-10 serum concentrations 19 and are epigenetically poised for ASC differentiation through T-bet-driven networks 20 .…”

“…EF response characterization has identified the pathway as peripherally focused, inflammatory, and highly associated with IL-6 and IP-10 (refs. 19,20,32 ). Both of these factors have now been identified as biomarkers of poor prognosis in the COVID-19 literature 1 and could be identified at increased expression in the CoV-A cluster (Fig.…”

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

“…). The common factors seem the combination of cytokine signals of IL‐21 and IFN‐γ and the signals via TLR and/or CD40, and cytokine alone is insufficient . The importance of IL‐21 is consistent with high expression of IL‐21 receptor and the IL‐21‐inducible gene signature in SLE CD11c + DN B cells .…”

“…Zumaquero et al. showed that the cocktail of TLR7‐ligand, BCR signal, IL‐21, IL‐2, BAFF and IFN‐γ strongly induced naïve B cells to differentiate into CD11c + DN B cells, and IFN‐γ was the most critical among these factors . The differences in the findings are likely caused by differences in the experimental protocols, including in vitro culture system, method to isolate naïve B cells, and the readout phenotype to define CD11c + DN B cells.…”

Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency

“…17 CD21-low B cells resemble autoreactive CD11c 1 B cells associated with systemic lupus erythematosus, and chronic viral infections have been reported to express the IFN-g inducible transcription factor Tbet and CXCR3. 14,19,38 IFN-g was recently reported to augment the development of autoreactive CD11c 1 B cells, 39 a pathophysiologic link that has also been proposed in CVID. 19 We show correlations of CXCL10 with aberrant T-cell populations in CVID as well as with CD21-low B cells and suggest that the CXCR3 axis is an attractive target for specific treatment to mitigate CVID-related immune dysregulation.…”