IFNAR signaling in fibroblastic reticular cells can modulate CD8⁺ memory fate decision

CD8⁺ memory T cells (T_M ) are crucial for long-term protection from infections and cancer. Multiple cell types and cytokines are involved in the regulation of CD8⁺ T cell responses and subsequent T_M formation. Besides their direct antiviral effects, type I interferons (IFN-I) modulate CD8⁺ T cell immunity via their action on several immune cell subsets. However, it is largely unclear how nonimmune cells are involved in this multicellular network modulating CD8⁺ T_M formation. Fibroblastic reticular cells (FRCs) form the 3D scaffold of secondary lymphoid organs, express the IFN-I receptor (IFNAR), and modulate adaptive immune responses. However, it is unclear whether and how early IFNAR signals in lymph node (LN) FRCs affect CD8⁺ T_M differentiation. Using peptide vaccination and viral infection, we studied CD8⁺ T_M differentiation in mice with an FRC-specific IFNAR deletion (FRC^ΔIFNAR ). We show here that the differentiation of CD8⁺ TCR-transgenic T cells into central memory cells (T_CM ) is enhanced in peptide-vaccinated FRC^ΔIFNAR mice. Conversely, vesicular stomatitis virus infection of FRC^ΔIFNAR mice is associated with impaired T_CM formation and the accumulation of vesicular stomatitis virus specific double-positive CD127^hi KLRG-1^hi effector memory T cells. In summary, we provide evidence for a context-dependent contribution of FRC-specific IFNAR signaling to CD8⁺ T_M differentiation.