T lineage commitment from human stem and progenitor cells in thymus, bone marrow, cord blood and mobilized peripheral blood.

A long-standing focus for our lab is to understand the biology of human hematopoietic stem cells and the process by which they embark on the first stages of lymphoid commitment, with a particular interest on human T cell development in the thymus. Although the conceptual foundations are very similar between the species, critical biological differences exist between murine and human hematopoiesis. By studying primary human thymus we identified and characterized CD34+ progenitor subpopulations that undergo specification and commitment to the T lineage (Hao et al, Blood 2008; Kohn et al, Nature Immunology 2012; Casero et al, Nature Immunology 2015). More recently our group developed an in vitro 3D model called the “Artificial Thymic Organoid” (ATO) which recapitulates the stages of T cell development and maturation in human (Seet et al, Nature Methods 2017) and mouse (Montel-Hagen et al, Cell Reports 2020) thymus. Because of its unique ability to generate mature T cells from uncommitted hematopoietic stem and progenitor cells, the ATO model has been used in a wide range of applications including the study of T cell differentiation from patients with genetic forms of T cell immune deficiency (Bosticardo and Notarangelo, Blood Advances 2020) and to understand metabolic events during T cell development (Sun et al, Fontiers of Immunology 2021; Abt and Radu et al, JCI 2022). We have now adapted the ATO system to efficiently generate mature T cells from human pluripotent stem cells (Montel-Hagen and Seet et al, Cell Stem Cell 2019), and are exploring this as a platform technology for in vitro derived T cell therapies.