Evaluating correlates of memory CD8 T cell tissue residence

Abstract

Since tissue resident memory CD8 T cells (Trm) play a specialized role in protection against peripheral re-infections and cancer, there is considerable interest in their identification. Although Trm are defined by their lack of circulation, migration is difficult to assess. Thus, residence is usually inferred by putative residence-defining molecular markers. However, these proxies for migration have not been rigorously authenticated. This thesis evaluates correlates of memory CD8 T cell residence and seeks to uncover molecular markers that accurately discern Trm across diverse conditions. We demonstrate that location, antigen distribution, and antigen persistence influence whether memory CD8 T cells are resident. We show that memory CD8 T cells integrate a constellation of inputs – location, stimulation history, antigen persistence, and environment – resulting in myriad differentiation states. We ascertain that current Trm-defining methodologies have several implicit limitations. We establish that solely relying on tissue location, a single-marker approach, or migration proxies defined in a different tissue or context can result in misinterpretations. We elucidate the transcriptional relationships among CD8 Trm in diverse conditions and identify two transcriptionally distinct subset of Trm. We define a unifying (pan-) Trm gene expression signature that more accurately discerns Trm from non-Trm in diverse conditions. We illustrate the application of this pan-Trm signature beyond mouse models by evaluating its expression in memory CD4 and CD8 human T cells isolated from various tissues. We determine and validate a flow cytometry panel of molecular markers that enables more accurate discernment of CD8 Trm across a range of conditions. Finally, we show that these molecular markers, albeit better, do not fully substitute for migration assays. We conclude that a set of molecular markers may fail to unambiguously identify Trm in all biological settings. This data reveals the broad adaptability of CD8 T cells to diverse stimulatory and environmental inputs and provides practical recommendations for evaluating Trm.