Trafficking of Lung-Migratory Cdc2s into the Spleen Following Influenza Virus Infection

Abstract Trafficking of antigen-bearing, migratory conventional dendritic cells type 1 (cDC1) and type 2 (cDC2) from the lung into the lung-draining mediastinal LN (mLN) is essential for priming T cell responses to influenza virus. In the absence of cDC1s and cDC2s, or when these are unable to traffic from the lung into the mLN, T cell responses are compromised, which highlights the importance of these DC subsets in the generation of T-cell-dependent immunity to influenza. Importantly, it is generally considered that cDCs shortly die after reaching the mLN and therefore do not recirculate back to the blood. Nevertheless, DCs purified from the spleen of intransally influenza-infected mice efficiently prime CD8+ T cell responses. Paradoxically, the two locations are not connected by the lymphatic vasculature and the intransally-administered antigens do not freely reach the blood circulation. Thus, is not clear how DCs in the spleen acquire influenza antigens following intranasal infection. Here we show that a fraction of the lung-migratory cDC2s that reach the mLN following influenza virus infection egress from the mLN, reenter the blood circulation and subsequently migrate into the spleen to prime CD8+ T cell Responses. Collectively, our results demonstrate a new paradigm of DC migration, offer new insights into how systemic T cell responses to influenza are initiated, and will ultimately reveal new strategies to elicit systemic responses to vaccination.