Type I IFN Drives Experimental Systemic Lupus Erythematosus by Distinct Mechanisms in CD4 T Cells and B Cells.

Autor: Klarquist J; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045; jared.klarquist@cuanschutz.edu., Cantrell R; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and., Lehn MA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and., Lampe K; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and., Hennies CM; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and., Hoebe K; Janssen Research and Development, Johnson & Johnson, Spring House, PA 19477., Janssen EM; Janssen Research and Development, Johnson & Johnson, Spring House, PA 19477.
Jazyk: angličtina
Zdroj: ImmunoHorizons [Immunohorizons] 2020 Mar 11; Vol. 4 (3), pp. 140-152. Date of Electronic Publication: 2020 Mar 11.
DOI: 10.4049/immunohorizons.2000005
Abstrakt: Myriad studies have linked type I IFN to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). Although increased levels of type I IFN are found in patients with SLE, and IFN blockade ameliorates disease in many mouse models of lupus, its precise roles in driving SLE pathogenesis remain largely unknown. In this study, we dissected the effect of type I IFN sensing by CD4 T cells and B cells on the development of T follicular helper cells (T FH ), germinal center (GC) B cells, plasmablasts, and antinuclear dsDNA IgG levels using the bm12 chronic graft-versus-host disease model of SLE-like disease. Type I IFN sensing by B cells decreased their threshold for BCR signaling and increased their expression of MHC class II, CD40, and Bcl-6, requirements for optimal GC B cell functions. In line with these data, ablation of type I IFN sensing in B cells significantly reduced the accumulation of GC B cells, plasmablasts, and autoantibodies. Ablation of type I IFN sensing in T cells significantly inhibited T FH expansion and subsequent B cell responses. In contrast to the effect in B cells, type I IFN did not promote proliferation in the T cells but protected them from NK cell-mediated killing. Consequently, ablation of either perforin or NK cells completely restored T FH expansion of IFNAR -/- T FH and, subsequently, restored the B cell responses. Together, our data provide evidence for novel roles of type I IFN and immunoregulatory NK cells in the context of sterile inflammation and SLE-like disease.
(Copyright © 2020 The Authors.)
Databáze: MEDLINE
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