Regulation of the germinal center response by T follicular helper cells and type I interferons

Sammanfattning: The protective effect of most currently available vaccines is dependent on high-affinity antibodies and long lived B cell
memory, which develop within organized structures of secondary lymphoid organs called germinal centers (GCs). GC
formation is supported by T follicular helper (Tfh) cells, a subset of CD4+ T cells that develop in parallel to other effector
T cells and specifically localizes to B cell follicles. The aim for the work presented in this thesis was to define how the GC
response and Tfh cell differentiation are regulated by innate effectors, such as conventional dendritic cells (cDCs) and type
I interferons (IFNs), in response to protein immunization adjuvanted by the dsRNA-analogue poly(I:C).
In paper I, we show that Tfh cells and GC B cell responses of the IgG1 isotype can develop normally in the absence of
cDCs when a sufficient amount of antigen, allowing initial T cell priming, is provided. In contrast, the concurrent Th1
cell differentiation is impaired together with a selective loss of IgG2c production. We also find that B cells, monocytes and
possibly plasmacytoid DCs (pDCs) redundantly can prime CD4+ T cells in the absence of cDCs, and thereby support
early expression of the Tfh cell-associated chemokine receptor CXCR5. In paper II we find that type I IFNs predominantly
promote IgG2c+ GC B cell differentiation and in this context function through both B cell intrinsic and extrinsic signaling.
While we provide evidence for that direct IFN-γ signaling in B cells controls switching to IgG2c, our results indicate that
type I IFNs regulate IgG2c-associated GC responses beyond isotype switching, as the magnitude of the GC B cell response
is reduced when type I IFNs, but not when IFN-γ, are absent. In contrast to IgG2c, switching to IgG1 is unaffected by
type I IFN deficiency, although the overall magnitude and quality of the IgG1 response also is affected when type I IFN
signaling is abrogated. Additionally, the formation of B cell memory appears to be impaired in the absence of type I IFNs.
In paper III, we demonstrate how clonal competition selectively affects Tfh cell differentiation, GC responses and
generation of IgG1+ GC B cells, while the generation of IgG2c+ GC B cells appears to be less affected.
Taken together, the work included in this thesis increase our understanding of how GC B cell responses and Tfh cell
development are regulated, and furthermore, it suggests that switching to IgG1 and IgG2c associated GC B cell fate
commitment may be differentially dependent on Tfh cells.