Extended Data Fig. 4. Cell type-specific responses to a cytokine can be exclusive to the cytokine or can be attributed to secondary effects from induced cytokines.

a-b, Examples of cell type-specific responses to a cytokine that are not observed in the responses to the other cytokines studied. a, Examples of cell type-specific gene regulation in response to IL-1α/β and exclusively to IL-1α/β. Left, Heatmaps showing differential expression of IL-1α/β-regulated genes relative to PBS treatment per cell type, highlighting cell type-specific responses to the same cytokines. Three independent mice for each cytokine treatment are shown in adjacent columns. Right, for the IL-1α/β-induced cell type-specific DEGs in the heatmaps, the plots show whether they can be induced by any other of the 86 cytokine stimulations. Color of square, log₂ fold change in each cytokine treatment relative to PBS; size of square, –log₁₀ transformed FDR-adjusted P-value obtained from two-sided Wilcoxon rank-sum test. Results with FDR < 0.05 and log₂FC > 0.5 are shown. IL-1α/β treatments are highlighted in gray. Cell types in columns on the left and rows on the right follow the same color code. Note that both IL-36α and IL-1α/β are proinflammatory cytokines in the IL-1 cytokine family. b, Examples of cell type-specific gene regulation in response to IFN-α1/β and exclusively to IFN-α1/β; following the same visualization as in a. Note that both IFN-κ and IFN-α1/β are type I interferons and share receptors. c-e, Examples of cell type-specific responses to a cytokine that can be attributed to secondary effects from induced cytokines. c, Heatmaps showing DEGs in response to IL-2, IL-12, IL−15, IL−18 relative to PBS treatment, highlighting different responses to the same cytokine in NK cells vs. other cell types. Heatmap for IFN-γ treatment is included as a comparison. Stat1 is known to be regulated by IFN-γ signaling. d, Violin plot showing Ifng gene expression in NK cells after each of the 86 cytokine treatments or PBS treatment. Samples with a high expression (>0.8 normalized expression units) are colored dark blue. e, Induction of IFN-γ signatures across cell types after each cytokine treatment. The IFN-γ signature is obtained for each cell type from the IFN-γ treatment. Expression of the signature is obtained from summing normalized expression units of all genes in the signature for each cell type. Significant (FDR < 0.01) responses are shown as squares, with color gradient representing average log₂FC in each cytokine treatment relative to PBS (capped at 50), and size representing –log₁₀ transformed FDR-adjusted P-value obtained from two-sided Wilcoxon rank-sum test. Cytokines inducing a high expression of Ifng are highlighted in gray in d and e. d and e are vertically aligned to illustrate that the cytokine treatments inducing an upregulation of Ifng in NK cells display a strong IFN-γ signature in other cell types.

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