BATF3-dependent induction of IL-27 in B cells bridges the innate and adaptive stages of the antibody response

Abstract

During the antibody response, B cells are exposed to innate and adaptive T cell stimuli, although it is unclear whether and how ensuing receptor signals are functionally integrated. We have identified IL-27 as the cytokine specifically secreted by B cells upon sequential stimulation with TLR ligands and CD154 plus IL-21, the hallmark factors of T follicular helper cells. B-cell IL-27 production is concomitant with increased Il27p28 locus accessibility and depends on newly induced transcription factor BATF3. IL-27-producing B cells are inefficient in antibody secretion, but cooperate with IFNγ to promote proliferation, survival, class-switching and plasma cell differentiation of their target B cells, leading to IgG responses to a conjugated hapten and virus infection. Thus, IL-27-producing B cells function as “helper” B cells that integrate the innate and adaptive stages to optimize antibody responses.One-sentence summaryB cells integrate innate TLR and adaptive CD40 signals to induce BATF3 transcription factor for production of IL-27, which together with INFγ optimizes antibody responses.

B cells promote CD8 T cell primary and memory responses to subunit vaccines

“…Moreover, while canonically pleotropic, the influence of IL-27 on cellular immunity, outside of subunit vaccination, is overwhelmingly suppressive, so that any T-cell-centric elimination of IL-27 signaling typically results in elevated lymphoproliferation and its related pathology. In addition to the findings we report here, we and our colleagues recently documented the extent of B-cell-produced IL-27 in virus-infected and TLR-agonist-treated mice ( Yan et al, 2020 ). In these studies, IL-27 was highly expressed in mice treated with a range of TLR agonists often used as adjuvants.…”

“…Whereas IL-15 and IL-27 are produced by cDC1s ( Kilgore et al, 2018 ; Sosinowski et al, 2013 ), other antigen (Ag)-presenting cells (APCs) including B cells, also have the capacity to make one or both cytokines. Indeed, one member of the IL-27 heterodimer, Ebi3 ( E pstein- B arr virus [EBV] i nduced gene 3), was originally isolated from EBV-infected B cells, and B cells produce IL-15 and IL-27 upon stimulation with Toll-like receptor (TLR) ligands or CD40L ( Schneider et al, 2011 ; Yan et al, 2020 ). Furthermore, B cell expression of IL-27 has been linked to CD8 T cell recovery after lymphoablation ( Ayasoufi et al, 2019 ), and T cell memory in IL-27Rα −/− hosts is functionally compromised ( Pennock et al, 2014 ).…”

LUBAC Suppresses IL-21-Induced Apoptosis in CD40-Activated Murine B Cells and Promotes Germinal Center B Cell Survival and the T-Dependent Antibody Response

“…Also along this line, preactivation of Sharpin +/+ or Sharpin cpdm B cells with CD154 plus IL-4 did not make them resistant to death induced by IL-21, the production of which lags the IL-4 production by NKT cells and Th2 cells before the GC reaction (15,54), indicating that sensitivity to IL-21-triggered death is an important feature intrinsic to GC B cells. By contrast, pre-activation by TLR ligands promoted the survival of B cells activated by suboptimal CD40 signaling (e.g., as initiated by aCD40) and IL-21, likely mediating their differentiation into IL-27-producing B cells (55). Finally, the ability of strong BCR crosslinking by aIgD/ dex to endow Sharpin cpdm B cells resistance to IL-21 suggests that BCR signaling partially contributed to the GC B cell survival in B-Sharpin cpdm mice, possibly by upregulating MYC (56).…”

Regulation of CD8 T cell by B-cells: A narrative review

“…Under the same experimental conditions, memory CD8 T cells were shown to lose persistently their responsiveness to IL-27 associated with an inability to secrete IL-10. IL-27 is produced by B lymphocytes upon stimulation of the toll-like receptor (TLR), CD40 and IL-21 ( 78 ). Klarquist and colleagues demonstrated that IL-27 derived from B cells is an important cytokine for the primary but not the memory response of CD8 T cells after vaccination ( 79 ).…”