Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells.

Stromal cells poised to defend: Fibroblastic reticular cells (FRCs) in lymph nodes help establish niches where productive cell interactions can engender effective immune defense. Perez-Shibayama et al. evaluated the contribution of type I interferons and interferon-stimulated genes to supporting normal FRC function by studying mice with conditional deletion of the type I interferon receptor (Ifnar) in FRCs. Single-cell RNA sequencing of Ifnar-deficient FRCs revealed baseline perturbations in FRC differentiation associated with changes in myeloid cell composition. Mice with Ifnar-deficient FRCs were compromised in their ability to control spread of a localized virus infection due, in part, to impaired CD8⁺ T cells displaying features of exhaustive activation. Sensing of type I interferons by FRCs is critical to maintaining secondary lymphoid tissues in a poised state ready to repel viral infections. Fibroblastic reticular cells (FRCs) are stromal cells that actively promote the induction of immune responses by coordinating the interaction of innate and adaptive immune cells. However, whether and to which extent immune cell activation is determined by lymph node FRC reprogramming during acute viral infection has remained unexplored. Here, we genetically ablated expression of the type I interferon-α receptor (Ifnar) in Ccl19-Cre⁺ cells and found that sensing of type I interferon imprints an antiviral state in FRCs and thereby preserves myeloid cell composition in lymph nodes of naive mice. During localized lymphocytic choriomeningitis virus infection, IFNAR signaling precipitated profound phenotypic adaptation of all FRC subsets enhancing antigen presentation, chemokine-driven immune cell recruitment, and immune regulation. The IFNAR-dependent shift of all FRC subsets toward an immunostimulatory state reduced exhaustive CD8⁺ T cell activation. In sum, these results unveil intricate circuits underlying type I IFN sensing in lymph node FRCs that enable protective antiviral immunity. [ABSTRACT FROM AUTHOR]