Priming of Long-Lived Memory CD8+ T cell Responses in the Spleen During Influenza Virus Infection

Abstract

Abstract CD8+ T cell responses to influenza virus infection are canonically known to be activated solely in the lung draining, mediastinal lymph node (mLN). Mechanistically, migratory dendritic cells (mDCs) are activated in the lungs and traffic to the mLN where they encounter cognate CD8+ T cells, initiating the heterogeneous response to influenza virus. As such, when mDCs are absent or when migration is inhibited, CD8+ T cell responses are compromised and the viral burden in the lungs increases. In contrast to the current paradigm, local priming of CD8+ T cells has been hypothesized to occur in the spleen, and mDCs are thought to die in the mLN shortly after trafficking. Therefore, how CD8+ T cells could be primed locally in the spleen has remained an unpopular hypothesis. Here we show using a mouse model of influenza infection, that mDCs not only prime CD8+ T cells in the mLN, but can also prime CD8+ T cell responses locally in the spleen. Mechanistically, we show that a portion of the mDCs trafficking to the mLN can egress the mLN, enter the blood via an S1P/S1PR dependent mechanism, and enter the spleen. CD8+ T cell responses initiated in the spleen are longer lived than mLN primed responses. Collectively, our results demonstrate a novel DC trafficking pathway and support a new paradigm for how heterogeneous T cell responses to influenza are initiated.