4-1BBL on CCR2-dependent cells selects NP366-specific CD8+ T cells for immunodominance during influenza infection 3086

Description Memory CD8+ T cells are crucial for cross-reactive protection against heterosubtypic influenza A virus (IAV) infection. The tumour necrosis factor receptor 4-1BB contributes to accumulation of antigen-specific CD8+ T cells during viral infection, however the pertinent source of its ligand 4-1BBL is unclear. We profiled the innate immune landscape of the murine lung during IAV infection using single-cell RNA sequencing and flow cytometry, identifying inflammatory monocyte-derived antigen-presenting cells (moAPCs) as the predominant expressors of 4-1BBL, with lower expression on classical DC. Given the numerical dominance of moAPCs in tissue during acute infection, we asked whether these two cellular sources of 4-1BBL may differentially impact antigen-specific CD8+ T cell accumulation. Using multiple mouse models of conditional 4-1BBL deletion, we showed that 4-1BBL on moAPCs selects NP366-specific CD8+ T effector and memory cells in the tissue for immunodominance, while 4-1BBL on DCs can support broader epitope specificities. Analysis of 4-1BB wildtype and knockout CD8+ T cells during infection suggests that 4-1BB signaling may enhance survival and mitochondrial fitness, rather than acting as a differentiation cue. Funding Sources Supported by Canadian Institutes for Health Research grants #FDN-143250 and PJT-178020 (to T.H.W), and Ontario Graduate Scholarship and Emerging & Pandemic Infections Consortium Doctoral Award to K.Y. T.H.W. holds the Canada research chair in anti-viral immunity at the University of Toronto.