All ETDs from UAB

Advisory Committee Chair

Andre Ballesteros-Tato

Advisory Committee Members

Frances Lund

Laurie Harrington

Amy Weinmann

Troy Randall

Craig Maynard

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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.

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