Type I interferons promote germinal centers through B cell intrinsic signaling and dendritic cell dependent Th1 and Tfh cell lineages

Dahlgren, Madelene W.; Plumb, Adam W.; Niss, Kristoffer; Lahl, Katharina; Brunak, Søren; Johansson-Lindbom, Bengt

Type I interferons (IFNs) play an essential role in antiviral immunity, correlate with severity of systemic autoimmune disease, and are likely to represent a key component of mRNA vaccine-adjuvanticity. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood due to pleiotropic effects in multiple cell types. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells. Type I IFN signaling in cDCs, distinct from cDC1, stimulates development of separable Tfh and Th1 cell subsets. However, Th cell-derived IFN-γ induces T-bet expression and IgG2c isotype switching prior to this bifurcation and has no evident effects once GCs and bona fide Tfh cells developed. This pathway acts in synergy with early B cell-intrinsic type I IFN signaling, which reinforces T-bet expression in B cells and leads to a selective amplification of the IgG2c+ GC B cell response. Despite the strong Th1 polarizing effect of type I IFNs, the Tfh cell subset develops into IL-4 producing cells that control the overall magnitude of the GCs and promote generation of IgG1 + GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through parallel Th1 and Tfh cell-dependent pathways.