Innate Antiviral Specialization of Ly6C+CD45+ Splenic Red Pulp Stroma Instilled by Subset-Specific Regulation of Cellular Sensitivity to Type I Interferons

Our understanding of splenic stromal cell composition and function remains incomplete. Here, we uncover that splenic red pulp stroma is phenotypically Ly6C+CD45+, due to acquisition of hematopoietic-derived CD45 via intercellular transfer in situ. Using a rectified gating strategy to integrate stroma with surface CD45 expression, we transcriptionally profiled the entire splenic mesenchymal cell compartment with single-cell resolution at steady state and upon viral infection. We show extensive functional heterogeneity of the white pulp-, red pulp- and perivascular stromal cell components and identify striking differences in innate antiviral response potential of distinct stromal subsets. We demonstrate that Ly6C+CD45+ red pulp stromal cells are selectively sensitized by tonic type I interferon signals, which licenses them with enhanced sensitivity to interferon stimulation in vivo and with vigorous antiviral gene response upon systemic infection. These results highlight a specialized contribution of stroma to the innate immune function of the splenic red pulp.