Fig. 3: Triplication of the Ifnr locus drives increased IFNR expression and exacerbated antiviral responses in a mouse model of DS.

a, gMFI relative to WT mice, as measured by flow cytometry, for IFNR proteins on CD45⁺ WBCs from heterozygous Ifnr knockout mice (WT^1xIfnrs, n = 5, 3 male and 2 female), WT (n = 8 for IFNAR1, 2 male and 6 female, n = 16 for IFNGR2, 10 male and 6 female), Dp16 (n = 7, 5 male and 2 female) and Dp16^2xIfnrs (n = 6 for IFNAR1, 4 male and 2 female; n = 8 for IFNGR2, 6 male and 2 female). Horizontal dashes indicate mean values. Significance determined by two-sided Mann–Whitney test. b, gMFI relative to WT, as measured by flow cytometry, for phosphorylated STAT1 in WBCs at baseline or after 30 min stimulation with IFN-α or IFN-γ. Number of animals—unstimulated WT (n = 25, 16 male and 9 female), Dp16 (n = 15, 7 male and 8 female) and Dp16^2xIfnrs (n = 8, 8 male); +IFN-α WT (n = 23, 14 male and 9 female), Dp16 (n = 12, 3 male and 9 female) and Dp16^2xIfnrs (n = 9, 9 male); +IFN-γ WT (n = 25, 16 male and 9 female), Dp16 (n = 12, 12 male) and Dp16^2xIfnrs (n = 7, 7 male). Significance determined by two-sided Mann–Whitney test. c, Heatmap displaying NES from GSEA with Hallmark gene sets of transcriptome fold-changes for the indicated comparisons in mesenteric lymph nodes, sorted by NES for Dp16/WT; *q < 0.1 defined by GSEA with Benjamini–Hochberg correction. d, Heatmaps (top) representing median RPKM expression z scores per genotype and sina plots (bottom) for example genes from the indicated gene sets; q values determined by DESeq2 with significance defined as q < 0.1 after Benjamini–Hochberg correction. e, Kaplan–Meier plot comparing survival across genotypes during chronic stimulation with the TLR3 agonist poly(I:C); significance determined by Mantel–Cox log-rank test. f, Percentage weight loss normalized to total number of poly(I:C) doses. For e and f, WT sham (n = 9, 2 male and 7 female), WT poly(I:C) (n = 13, 6 male and 7 female), Dp16 poly(I:C) (n = 9, 6 male and 3 female), Dp16^2xIfnrs poly(I:C) (n = 13, 6 male and 7 female). g, TNF protein in serum on day 3 of poly(I:C) exposure, WT sham (n = 6, 2 male, 4 female), WT poly(I:C) (n = 7, 3 male, 4 female), Dp16 poly(I:C) (n = 6, 5 male, 1 female) and Dp16^2xIfnrs poly(I:C) (n = 6, 3 male and 3 female). In f and g, horizontal dashes indicate group means and P values for pairwise comparisons were determined by two-sided Mann–Whitney test, with significance set at P < 0.05. h, Scatter plot comparing TNF concentration and percent weight loss on day 3 of poly(I:C) exposure (n = 25 animals, numbers by genotype and sex as in g), with simple linear regression fit line. ρ and P values from Spearman correlation with permutation test. gMFI, geometric mean fluorescent intensities.

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