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Abstract

T cells have a major role in the adaptive immune response, where they eliminate infectious agents and malignant cells by specific recognition of non-self antigens. Besides this general function in the immune response, T cells also have diverse tissue-specific functions. This has been well described for regulatory T cells, which are not only essential for the control of the immune response, but are also involved in maintaining tissue homeostasis. However, most evidence comes from bulk experiments in mice resulting in limited resolution of T cell subsets and it is unknown whether Treg cells with a similar tissue adaptation program also exist in humans. Especially epigenetic adaptations underlying observed transcriptional changes in T cells from lymphoid and peripheral tissues remain incompletely understood.

In this work, I analyzed single cell ATAC sequencing data of flow-sorted CD4+ and CD8+ T cells from lymphoid and non-lymphoid tissues to investigate the molecular programs driving T cell adaptation to peripheral tissues. The availability of both human and murine samples allowed me to describe commonalities and differences in their T cell biology. In addition, I used these T cell atlases under homeostasis together with several T cell datasets from tumors to gain insights on shared chromatin accessibility changes in the tumor microenvironment.

My analysis showed the presence of human tissue Treg cells that have many commonalities with their murine counterparts. These include a conserved epigenetic signature with enriched footprint of transcription factor BATF. I further identified potential tissue Treg precursor cells in human peripheral blood and mouse spleen sharing increased chromatin accessibility at the locus encoding chemokine receptor CCR8. While murine tissue Treg cells are T helper 2 cell-biased, human Treg cells in peripheral tissues more closely resemble T follicular helper cells in their ATAC profile. Within the CD8+ T cell compartment, I showed that murine and human peripheral tissues harbor a population of PD1+TOX+ CD8+ T cells with epigenomes denoting a concurrent activation and exhaustion state. PD1+TOX+ CD8+ T cells shared chromatin features of tissue adaptation and BATF dependence with tissue Treg cells. I further contextualized epigenetic adaptation observed in tissue-repair associated Treg cells in a comprehensive view on immune cells that suggests commonalities not only with CD8+ T cells and innate lymphoid cells, but also with several myeloid cell subsets. Eventually, through comparison of T cells from healthy and tumor tissues, I showed that Treg and PD1+TOX+ CD8+ T cells from tumors also maintain a tissue adaptation program.