Tissue Resident Memory (Trm) CD8+ T cells: Genome-wide dissection of cellular differentiation and heterogeneity

Objectif

Tissue-resident memory (Trm) cells are non-circulating T lymphocytes of non-lymphoid tissues and organs that provide localized protection at barrier surfaces such as skin, gut and lungs. In human skin, Trm cells represent the predominant lymphocyte population, comprising subsets with different cytokine profiles and cytotoxic capacity. They represent an integral part of barrier immunity, mounting tailored responses to diverse pathogens, but potentially also eliciting immune pathology. Trm cell differentiation, effector mechanisms and cellular interactions remain poorly defined. I aim to decipher cytotoxic Trm cell biology in greater depth, unravelling the epigenetic framework of phenotypically and functionally distinct CD8+ Trm populations. I will rely on state-of-the-art methodologies at the host institution. Through unique collaborations and a multidisciplinary approach encompassing advanced flow cytometry, cell sorting and high-throughput sequencing, I propose to map genome-wide chromatin accessibility in skin and gut Trm cell subsets. Identification of regulatory elements critical for cell functions coupled with analyses of transcription factor binding promise to unravel the molecular mechanisms defining Trm cell ontogeny, function and tissue-specific imprinting. Moreover, with potential application to limited patient samples, single-cell RNA sequencing of cytokine-producing cells will provide a map of Trm cell heterogeneity with unprecedented resolution. This project will illuminate the role of the microenvironment in shaping tissue-resident memory, with ultimate goals to understand Trm cell-related diseases and determine common denominators required to establish tissue residency and provide basis for generating and shaping Trm cells in future cellular immunotherapies. Being at the forefront of the research on the epigenetic differentiation processes of lymphocytes, I am determined to build a strong basis for a future career as a young independent scientist.