4-1BBL on Monocyte Lineage Cells Rather Than on Classical Dendritic Cells Drives CD8+ T Cell Accumulation in the Respiratory Tract and Protects from Severe Respiratory Influenza Infection.

Seasonal epidemics and the persistent threat of a pandemic provide a strong impetus to understand mechanisms of protection against influenza infection. T cell intrinsic signaling through the TNFR superfamily member 4-1BB is critical for the accumulation of antigen-specific CD8+ effector and memory T cells in the lung and protection from influenza A virus (IAV). However, the APCs that provide 4-1BB ligand (4-1BBL) have not been definitively characterized. Here, using single-cell RNA sequencing and multiparameter flow cytometry, we define murine monocyte lineage cell (MC) and classical dendritic cell (cDC) populations in the lung during acute IAV infection and show that 4-1BBL is more highly expressed on CD64+MAR-I+CD26- inflammatory MCs than on MHCIIhiCD11c+CD26+ cDCs following IAV infection. Mixed bone marrow chimeras, in which 4-1BBL is only absent on Ccr2-dependent cells, and Cre-driven deletion using Ccr2- or Zbtb46-cre demonstrate that 4-1BBL on MCs rather than cDCs is important for the accumulation of nucleoprotein (NP)-specific CD8+ effector and tissue-resident memory T cells. Importantly, 4-1BBL on Ccr2-dependent cells is critical for mouse survival following severe IAV infection. These findings reveal a division of labor between cDC and MCs, with infMCs uniquely providing 4-1BBL to increase CD8+ T cell accumulation in the lung and protect against severe IAV infection.