Interferon-Alpha Triggers B Cell Effector 1 (Be1) Commitment

Abstract

B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-γ play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-α triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-γ gene imprinting factors. IFN-α primed naive B-cells for IFN-γ production and increased IFN-γ gene responsiveness to IL-12. IFN-γ continues this polarization by re-inducing T-bet and up-regulating IL-12Rβ2 expression. IFN-α and IFN-γ therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-α, IFN-γ and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.

CD23+CD21highCD1dhigh B Cells in Inflamed Lymph Nodes Are a Locally Differentiated Population with Increased Antigen Capture and Activation Potential

“…The relationship between inflammation and B cell function has been the focus of significant interest because of its implications for normal immune responses, the onset and amplification of autoimmune states, and the design of novel immune modulators and adjuvants (32, 35, 70). Inflammatory signals can have significant effects on B cell development and have been shown to affect peripheral B cell homeostasis by modulating BCR repertoire and selection/tolerance (33–34, 36). In addition, B cells can have active roles in regulating inflammatory states by their ability to secrete pro- or anti-inflammatory cytokines, and to influence T cell subset differentiation (7, 29, 48, 71–74).…”

T-bet-expressing B cells during HIV and HCV infections

“…IFNg is a potent inducer of T-bet expression in B cells [7,18], and the early appearance and continued presence of this cytokine could promote T-bet + B cell development during HIV infection. Interferon alpha (IFNa), which is produced at high levels by plasmacytoid dendritic cells (pDCs) during HIV infection [79,80], could also support T-bet + B cell differentiation: IFNa supports antiviral B cell responses in mouse models [81], and is known to induce T-bet expression in human B cells and prime them for IFNg production [82]. The HIV virus itself provides sufficient quantities of TLR7 and TLR9 ligands during infection that could indirectly support B cell T-bet induction by stimulating pDCs to produce IFNa [79,83–86].…”

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

“…Interestingly, type I IFN previously has been shown to skew follicular B cell Ab responses against TI-2 Ags toward an IgG2c isotype (48). Type I IFN is produced during Plasmodium infection (49) and permits B cells to become responsive to IL-12 and become B effector 1 (Be1) cells (50). Sustained expression of IFN-g and T-bet by Be1 cells is maintained through a signaling loop involving dendritic cells (DCs) producing IL-12 and IL-18 leading to expression of IFN-g by Th1 cells and B cells (23,51).…”