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Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity
- Source :
- J Immunol
- Publication Year :
- 2020
- Publisher :
- The American Association of Immunologists, 2020.
-
Abstract
- TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-γ signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-γ signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-γ reporter mice show that CD4+ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-γ. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-γR indicates that TLR7-induced IFN-γ activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-γ signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-γ and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.
- Subjects :
- Immunology
Cell
Autoimmunity
Biology
Lymphocyte Activation
Article
Interferon-gamma
Mice
03 medical and health sciences
0302 clinical medicine
Plasma cell differentiation
medicine
Animals
Lupus Erythematosus, Systemic
Immunology and Allergy
STAT1
B cell
B-Lymphocytes
Membrane Glycoproteins
virus diseases
Germinal center
TLR7
Germinal Center
Cell biology
medicine.anatomical_structure
Toll-Like Receptor 7
IFNGR1 Gene
Interferon Type I
biology.protein
Signal transduction
Signal Transduction
030215 immunology
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 204
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi.dedup.....507e31cc8c01f2db74ca1c8a19840d88
- Full Text :
- https://doi.org/10.4049/jimmunol.1901175