Priming by Lung-Mdcs in the Spleen Initiates CD8+T Cell Responses During Influenza Infection

Abstract Initiation of CD8+ T cell responses to influenza virus requires the trafficking of activated lung-migratory dendritic cells (mDCs) from the lung into the lung-draining mediastinal LN (mLN) in response to influenza virus infection in the lungs. As such, when mDCs are absent or are unable to migrate into the mLN, T cell responses are severely compromised, and the mortality rate increases in mouse models of influenza infection. Importantly, it is generally considered that mDCs die shortly after reaching the mLN. Thus, the current paradigm suggests that priming of influenza-specific T cell responses by lung-mDC takes place entirely in the mLN. Recent reports have suggested that CD8+ T cell responses may also be initiated in the spleen, although influenza derived antigens to not freely reach the spleen or blood circulation. Together, these data and recent reports highlight a gap in knowledge of basic antigen trafficking. We show here, that a fraction of the lung mDCs egress the mLN, enter the blood circulation, and subsequently traffic to the spleen, where they prime influenza-specific CD8+ T cell responses. Mechanistically, the exit of mDCs from the mLN is controlled by Sphingosine-1-Phosphate Receptors (S1PRs) expressed by lung-mDCs, and when these receptors are blocked, CD8+ T cell activation is conjointly blocked. Collectively, our results demonstrate a novel DC trafficking pathway and support a new paradigm for the initiation of CD8+ T cell responses, where a portion of the total response, including the memory response, is primed in the spleen instead of only the mLN.