Embryonic origins of T cells

PROJECT SUMMARY / ABSTRACT T lymphocytes are adaptive immune cells that protect the host against a diverse array of pathogens. In the last decade, immunologists have started to learn how to harness the function of T cells for immune benefit, which has revolutionized the field of immunology and changed the way we treat a variety of immune-mediated diseases, including cancer. However, recent discoveries in the fields of immunology and hematopoiesis suggest that our current model of T cell development is out-of-date, which may be contributing to inefficient treatment approaches to immune-mediated diseases. Up until now, the dogma in the field has been that all T cells are generated from bone marrow-derived hematopoietic stem cells (HSCs), and that the T cell compartment is comprised of a single lineage of T cells that are created equally. However, stem cell biologists have recently discovered that there are a wide variety of non-HSC progenitors at different anatomical sites in early life that can produce T cells. In separate studies, immunologists have learned that T cells made in early life persist into adulthood and exhibit unique roles during infection and disease. The stem cell biologists have yet to characterize the T cells made by non-HSC progenitors, and the immunologists have yet to map the precise hematopoietic origins of T cells found in adulthood. Essentially, the fields of hematopoiesis and immunology are not in sync, preventing us from updating the current model of T cell development. Our goal is thus to sync the fields, dissecting out the unique lineages of T cells made from different non-HSC and HSC progenitors in early life to determine how the function of T cells in adults is linked to their developmental origins. In Aim 1, we will establish what types of T cells can be made from various embryonic progenitors. In Aim 2, we will focus on a particular type of T cells (CD8+ T cells) and examine how their immune function and programming correspond to their derivation from non-HSC and HSC progenitors in early life. To accomplish these goals, we will employ embryo dissections, artificial thymic organoids, cell transplantations, and single cell sequencing, ultimately propelling us toward a new paradigm for T cell development. Once this paradigm is established, we expect to (i) uncover lineages of T cells ideally suited for immunotherapies, (ii) predict how patients will respond to current treatment strategies, and (iii) learn how to fully regenerate the T cell compartment after immune reconstitution therapies.