Lung dendritic cells migrate to the spleen to prime long-lived memory CD8+ T cell precursors after influenza virus infection

CD8+ T cell responses to pulmonary challenges are primed by lung-migratory dendritic cells (mDCs), which capture antigens in the lung and migrate to the lung-draining mediastinal lymph node (med-LNs) to activate T cells. Notably, the lung and the spleen are not connected by the lymphatic vasculature. Thus, the current paradigm suggests that the med-LN is the only site for T cell priming to viruses that are restricted to the respiratory tract. Our results challenge this “LN-centric” paradigm. Using an influenza virus infection, we show here that lung-mDCs egress the med-LN and traffic to the spleen, where they prime influenza-specific CD8+ T cells. Importantly, CD8+ T cells primed in the spleen are transcriptionally different and have enhanced ability to differentiate into long-lived memory cells compared to med-LN-primed counterparts. Thus, our data reveal a previously ignored lung-mDC trafficking pathway that connects the lung with the spleen and has profound immunological implications. Overall design: OTI cells (CD45.2) were adoptively transferred into day 1 PR8-infected CD45.1 mice. The next day, recipient mice were i.t treated with 60 µg of OVA and activated CD69+CD62Llo OTI cells were sorted from the spleen (spleen-primed, SP-P) and med-LN (med-LN-primed, LN-P) 24 later. Naïve OTI cells were also purified from naïve OTI mice and RNA-seq was performed.