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Type I Interferons Promote Germinal Centers Through B Cell Intrinsic Signaling and Dendritic Cell Dependent Th1 and Tfh Cell Lineages

Dahlgren, Madelene W. LU orcid ; Plumb, Adam W. ; Niss, Kristoffer ; Lahl, Katharina LU ; Brunak, Søren and Johansson-Lindbom, Bengt LU (2022) In Frontiers in Immunology 13.
Abstract

Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. 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 in B cells prior to this bifurcation and has no... (More)

Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. 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 in B cells 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 divergent Th1 and Tfh cell-dependent pathways.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
antibody responses, germinal center (GC) B cells, IgG subclass antibodies, Tfh cells, Th1 cells, Type I Interferons
in
Frontiers in Immunology
volume
13
article number
932388
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85134799358
  • pmid:35911733
ISSN
1664-3224
DOI
10.3389/fimmu.2022.932388
language
English
LU publication?
yes
id
bafa582f-b8d0-4f59-995c-18c1f0988887
date added to LUP
2022-09-15 15:01:38
date last changed
2024-06-23 22:01:21
@article{bafa582f-b8d0-4f59-995c-18c1f0988887,
  abstract     = {{<p>Type I interferons (IFNs) are essential for antiviral immunity, appear to represent a key component of mRNA vaccine-adjuvanticity, and correlate with severity of systemic autoimmune disease. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood. 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 in B cells 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<sup>+</sup> 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<sup>+</sup> GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through divergent Th1 and Tfh cell-dependent pathways.</p>}},
  author       = {{Dahlgren, Madelene W. and Plumb, Adam W. and Niss, Kristoffer and Lahl, Katharina and Brunak, Søren and Johansson-Lindbom, Bengt}},
  issn         = {{1664-3224}},
  keywords     = {{antibody responses; germinal center (GC) B cells; IgG subclass antibodies; Tfh cells; Th1 cells; Type I Interferons}},
  language     = {{eng}},
  month        = {{07}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Type I Interferons Promote Germinal Centers Through B Cell Intrinsic Signaling and Dendritic Cell Dependent Th1 and Tfh Cell Lineages}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.932388}},
  doi          = {{10.3389/fimmu.2022.932388}},
  volume       = {{13}},
  year         = {{2022}},
}