NK cells contribute to reovirus-induced IFN responses and loss of tolerance to dietary antigen
Pamela H. Brigleb, Elaine Kouame, Kay L. Fiske, Gwen M. Taylor, Kelly Urbanek, Luzmariel Medina Sanchez, Reinhard Hinterleitner, Bana Jabri, Terence S. Dermody
Pamela H. Brigleb, Elaine Kouame, Kay L. Fiske, Gwen M. Taylor, Kelly Urbanek, Luzmariel Medina Sanchez, Reinhard Hinterleitner, Bana Jabri, Terence S. Dermody
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Research Article Immunology Virology

NK cells contribute to reovirus-induced IFN responses and loss of tolerance to dietary antigen

Abstract

Celiac disease is an immune-mediated intestinal disorder that results from loss of oral tolerance (LOT) to dietary gluten. Reovirus elicits inflammatory Th1 cells and suppresses Treg responses to dietary antigen in a strain-dependent manner. Strain type 1 Lang (T1L) breaks oral tolerance, while strain type 3 Dearing reassortant virus (T3D-RV) does not. We discovered that intestinal infection by T1L in mice leads to the recruitment and activation of NK cells in mesenteric lymph nodes (MLNs) in a type I IFN–dependent manner. Once activated following infection, NK cells produce type II IFN and contribute to IFN-stimulated gene expression in the MLNs, which in turn induces inflammatory DC and T cell responses. Immune depletion of NK cells impairs T1L-induced LOT to newly introduced food antigen. These studies indicate that NK cells modulate the response to dietary antigen in the presence of a viral infection.

Authors

Pamela H. Brigleb, Elaine Kouame, Kay L. Fiske, Gwen M. Taylor, Kelly Urbanek, Luzmariel Medina Sanchez, Reinhard Hinterleitner, Bana Jabri, Terence S. Dermody

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Figure 4

Type I IFN modulates NK cell recruitment, activation, and type II IFN responses in MLNs.

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Type I IFN modulates NK cell recruitment, activation, and type II IFN re...
WT or IFNAR–/– mice were PO inoculated with 1 × 108 PFU of T1L or PBS as a control. At 2 dpi, MLNs were resected and processed for flow cytometry (n = 5–6). (A) Viral titers in MLNs were determined by plaque assay at 2 dpi (n = 6) (B) Number of NK cells (CD45+ TCRβ– NK1.1+) and number of NK cells expressing activation marker CD69 (CD45+ TCRβ– NK1.1+ CD69+) in MLNs. (C and D) MLN cell suspensions (5 × 106 cells) were stimulated with PMA and ionomycin at 37°C for 4 hours, and cells were assessed for IFN-γ production by intracellular cytokine staining (n = 6–8). (C) Number, percentage, and MFI of NK cells (CD45+ TCRβ– NK1.1+) that express intracellular IFN-γ. (D) Contour plot of intracellular IFN-γ expression by a representative sample of NK cells (CD45+ TCRβ– NK1.1+). Results are presented as mean values. Data are shown as mean ± SEM. Statistical significance was calculated using Student’s t test in A and 1-way ANOVA with Tukey’s multiple comparisons test in B–D. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.