tetano
Editor, Senior Moderator
Mucosal Immunol
. 2026 Jul 1:100374.
doi: 10.1016/j.mucimm.2026.100374. Online ahead of print.
4-1BBL on monocyte lineage cells rather than on classical dendritic cells drives CD8[SUP]+[/SUP] T cell accumulation in the respiratory tract and protects from severe respiratory influenza infection
Karen K M Yeung[SUP] 1 [/SUP], Seungwoo Lee[SUP] 1 [/SUP], Nathalia V Batista[SUP] 1 [/SUP], Razieh Eshraghisamani[SUP] 1 [/SUP], Tianning Yu[SUP] 1 [/SUP], Tobias M Hohl[SUP] 2 [/SUP], Tania H Watts[SUP] 3 [/SUP]
Affiliations
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[SUP]+[/SUP] 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[SUP]+[/SUP]MAR-I[SUP]+[/SUP]CD26[SUP]-[/SUP] inflammatory MCs than on MHCII[SUP]hi[/SUP]CD11c[SUP]+[/SUP]CD26[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] T cell accumulation in the lung and protect against severe IAV infection.
Keywords: 4-1BBL; Dendritic cells; Influenza a virus; Monocyte lineage cells; T cells.
. 2026 Jul 1:100374.
doi: 10.1016/j.mucimm.2026.100374. Online ahead of print.
4-1BBL on monocyte lineage cells rather than on classical dendritic cells drives CD8[SUP]+[/SUP] T cell accumulation in the respiratory tract and protects from severe respiratory influenza infection
Karen K M Yeung[SUP] 1 [/SUP], Seungwoo Lee[SUP] 1 [/SUP], Nathalia V Batista[SUP] 1 [/SUP], Razieh Eshraghisamani[SUP] 1 [/SUP], Tianning Yu[SUP] 1 [/SUP], Tobias M Hohl[SUP] 2 [/SUP], Tania H Watts[SUP] 3 [/SUP]
Affiliations
- PMID: 42386082
- DOI: 10.1016/j.mucimm.2026.100374
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[SUP]+[/SUP] 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[SUP]+[/SUP]MAR-I[SUP]+[/SUP]CD26[SUP]-[/SUP] inflammatory MCs than on MHCII[SUP]hi[/SUP]CD11c[SUP]+[/SUP]CD26[SUP]+[/SUP] 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[SUP]+[/SUP] 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[SUP]+[/SUP] T cell accumulation in the lung and protect against severe IAV infection.
Keywords: 4-1BBL; Dendritic cells; Influenza a virus; Monocyte lineage cells; T cells.