Prlic, MartinMaurice, Nicholas Joseph2022-01-262022-01-262021Maurice_washington_0250E_23664.pdfhttp://hdl.handle.net/1773/48299Thesis (Ph.D.)--University of Washington, 2021Memory T cells (Tmem) are best understood as highly specific killers, using their T cell receptor (TCR) to identify and rapidly eliminate infected or transformed cells. Although T¬mem are best understood through the lens of TCR-mediated activation, it is not the lynchpin of their function. Tmem can also respond to pro-inflammatory cytokines in the absence of activating TCR signals, termed bystander activation. Although this phenomenon was described over 20 years ago, it was thought to be of little biologic significance until it was shown that bystander activated Tmem could kill using TCR-independent mechanisms. These killing programs were best understood during systemic and/or chronic inflammation, leading many to classify bystander-mediated killing as an “immunologic accident” resulting from astoundingly high levels of inflammation. The full gamut of circumstances in which bystander activation can occur, as well as the signals governing it, remain unclear. Here we address basic questions in bystander T cell biology: 1) in what biological contexts does bystander activation occur, 2) how can limited inflammation beget bystander activation, 3) what fate changes accompany bystander activation, and 4) do mechanisms that attenuate/control bystander activation exist? Using both clinical vaccine samples and mouse models, we demonstrate that bystander activation is not a niche phenomenon but can also arise during dose- and anatomically-restricted inflammation. This hinges on CXCR3-mediated recruitment of Tmem to sites of early immune activation, at where they become bystander activated by pro-inflammatory cytokines and contribute to localized target killing. While induction of cytotoxicity is the best-known consequence of bystander activation, we demonstrate that other fates, like tissue retention, can be elicited by inflammation alone. Using a multi-omics approach, we demonstrate that homeostatic cytokine networks exist in healthy human placental tissues, which sufficiently bystander activate Tmem without precipitating cytotoxicity and tissue pathology. We show this to result from cooperation between anti-inflammatory cytokines and metabolites, which restrain bystander-mediated cytotoxicity without forfeiting other activation-induced programs of tissue retention and surveillance. Together, we show that bystander activation is an intentional program oft used to maximally leverage Tmem in the absence of TCR agonism and identify mechanisms to better wield or restrain this population therapeutically.application/pdfen-USnoneImmunologyMolecular and cellular biologyThesis