Memory CD8+ T cells are formed after pathogen clearance in acute infection to survey the body and mount a faster, stronger response upon reexposure to the pathogen. These memory CD8+ T cells can take residence in peripheral tissue as tissue resident memory T cells (TRM) that can act as a first-line of defense against viral infection and tumor recurrence within their respective tissues. For TRM cells to take up residence in different tissues, they must adapt their transcriptional, metabolic, and functional states to persist in widely varying architectural and metabolic environments. Indeed, while TRM cells from different tissues exhibit common transcriptional signatures, they also display heterogeneity in metabolic gene expression that likely reflects adaptation to the different tissue environments. Understanding how T cells adapt to various metabolic environments would broaden our knowledge of organ-specific immunity and provide stronger protections against chronic infection and tumors. To study how TRM cells adapt to varying metabolic conditions, we seek to study how TRM cells take up residence in the liver, which is organized into distinguishable metabolic zones. The liver produces bile acids (BAs) to aide in digestion, but BAs can induce a variety of responses and stresses in cells. Analysis of RNA sequencing data showed that liver TRM cells exhibit a high expression of bile acid receptors and transporters that reflect the high bile acid content in the liver. In particular, they express the bile acid receptors CAR and TGR5, and the bile acid transporter MDR1, which play roles in bile acid sensing and homeostasis. What is unknown in the field is how TRM adaptation to the liver by expressing these receptors affects their formation, function and survival. We hypothesize that liver CD8+ TRM cells display heterogeneity within the liver reflective of the metabolic zones they inhabit, and express CAR, MDR1, and TGR5 in order to adapt the bile acid-rich environment of the liver. To examine this idea, we will first profile the heterogeneity of TRM with a combination of imaging mass spectrometry, flow cytometry, Seahorse assays, and RNA sequencing to correlate expression of metabolic genes and immunological function in TRM cells with their location within the liver. Next, we will explore the specific roles of CAR and MDR1 in TRM adaptation and function through flow cytometry, mass spectrometry, Seahorse assays, and RNA sequencing. We will similarly study TGR5, which is highly expressed on liver TRM cells, but has been reported to have anti-inflammatory functions. These results could lead to a better understanding of how TRM cells adapt to organ-specific metabolic environments, and the development of novel vaccination and therapeutic strategies to confer protection against liver infection and cancer.
In conferring immunological memory after pathogen clearance, CD8+ T cells take up residence in peripheral tissues to serve as a first-line guard against rechallenge against viral infection or tumors. To take residence in different tissues, these tissue resident memory T cells (TRM) must adapt to the local tissue environment in order to persist. Understanding how TRM cells adapt to different metabolic conditions will enhance our understanding of how these cells provide organ-specific immunity against infection, cancer, and inflammatory metabolic diseases.
