Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Initiation of CD8+ T cell responses to influenza virus infection requires the trafficking of activated lung-migratory dendritic cells (mDCs) from the lung into the lung-draining mediastinal LN (med-LN). As such, when mDCs are absent from the lungs or are unable to migrate into the med-LN, 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 med-LN. Thus, the current paradigm suggests that priming of all subsets of influenza-specific CD8+ T cell responses by mDCs takes place solely in the med-LN. Recent reports have suggested that local activation of CD8+ T cell responses also occurs 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 antigen-bearing lung mDCs in the med-LN egress, enter the blood circulation, and subsequently traffic to the spleen to prime influenza-specific CD8+ T cell responses. Mechanistically, the exit of mDCs from the med-LN is controlled by Sphingosine-1-Phosphate Receptors (S1PRs), expressed by lung-mDCs in the med-LN. When these receptors are blocked, CD8+ T cells in the spleen are consequently not activated. CD8+ T cells primed in the med-LN and spleen differ transcriptionally, but both contribute to the responding effector population in the lungs. Memory CD8+ T cells primed in these locations differ in that spleen-primed cells are enriched in the long-lived memory cell compartment and respond more robustly to rechallenge. Collectively, our results demonstrate a novel DC trafficking pathway and support a new paradigm for the initiation of CD8+ T cell responses. In this model, a portion of the total CD8+ T cell response is primed in the spleen instead of exclusively in the med-LN and spleen-primed cells make up the longer-lived memory CD8+ T cell compartment.
Jenkins, Meagan, "Local Priming Of Long-Lived Tcf1+ Memory Cd8+ T Cell Responses In The Spleen During Influenza Virus Infection By Lung Derived Migratory Dendritic Cells" (2021). All ETDs from UAB. 813.