A new model of human lymphopoiesis across development and aging

• Published in: Trends in immunology Vol. 45; no. 7; pp. 495 - 510
• Main Authors: Alhaj Hussen, Kutaiba, Louis, Valentine, Canque, Bruno
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2024
• Subjects: age-related changes in lymphocyte production patterns; Aging - immunology; Animals; B-Lymphocytes - immunology; Cell Differentiation; cell-intrinsic versus extrinsic regulation; early lymphoid progenitors; human lymphopoiesis; Humans; Killer Cells, Natural - immunology; lymphoid development architecture; lymphoid differentiation trajectories; Lymphoid Progenitor Cells - cytology; Lymphoid Progenitor Cells - immunology; Lymphoid Progenitor Cells - metabolism; Lymphopoiesis; multi-lymphoid progenitors; thymus colonization; lymphoid development architecture; cell-intrinsic versus extrinsic regulation; thymus colonization; age-related changes in lymphocyte production patterns; early lymphoid progenitors; lymphoid differentiation trajectories; human lymphopoiesis; multi-lymphoid progenitors
• ISSN: 1471-4906; 1471-4981; 1471-4981
• DOI: 10.1016/j.it.2024.05.007

We propose a model of human lymphopoiesis of bipartite organization stemming from founder populations of CD127/interleukin (IL)7R– or CD127/IL7R+ early lymphoid progenitors (ELPs) polarized toward the T-natural killer (NK)/innate lymphoid cell (ILC) or B lineages, respectively.CD127/IL7R– and CD127/IL7R+ ELPs originate from CD117lo multi-lymphoid progenitors (MLPs) and are subject to a differential Flt3 ligand-dependent versus cell-intrinsic regulation.CD117lo MLPs may differentiate though independent direct or stepwise pathways.CD117lo MLPs undergo profound changes across ontogeny in terms of relative percentages, immunophenotypes, and differentiation potentials.The passage to postnatal life coincides with a transition from multilineage to B lineage-biased lymphopoiesis, reflected by an immunophenotypic CD7-to-CD10 shift of lymphoid progenitors.Ontogeny-related changes in the pattern of lymphocyte production might be developmentally imprinted at the hematopoietic stem cell (HSC) stage. The conceptual advances presented here highlight a previously underappreciated complexity of human lymphopoiesis, in terms of both developmental architecture and dynamics across ontogeny. Understanding the gene regulatory networks driving the proposed direct or stepwise emergence of CD117lo multi-lymphoid progenitors, as well as the changes in representation, immunophenotype, and differentiation potential of CD127/IL7R–/+ early lymphoid progenitors during development and aging, has important basic and translational implications. Over the past decade our research has implemented a multimodal approach to human lymphopoiesis, combining clonal-scale mapping of lymphoid developmental architecture with the monitoring of dynamic changes in the pattern of lymphocyte generation across ontogeny. We propose that lymphopoiesis stems from founder populations of CD127/interleukin (IL)7R– or CD127/IL7R+ early lymphoid progenitors (ELPs) polarized respectively toward the T-natural killer (NK)/innate lymphoid cell (ILC) or B lineages, arising from newly characterized CD117lo multi-lymphoid progenitors (MLPs). Recent data on the lifelong lymphocyte dynamics of healthy donors suggest that, after birth, lymphopoiesis may become increasingly oriented toward the production of B lymphocytes. Stemming from this, we posit that there are three major developmental transitions, the first occurring during the neonatal period, the next at puberty, and the last during aging. Over the past decade our research has implemented a multimodal approach to human lymphopoiesis, combining clonal-scale mapping of lymphoid developmental architecture with the monitoring of dynamic changes in the pattern of lymphocyte generation across ontogeny. We propose that lymphopoiesis stems from founder populations of CD127/interleukin (IL)7R– or CD127/IL7R+ early lymphoid progenitors (ELPs) polarized respectively toward the T-natural killer (NK)/innate lymphoid cell (ILC) or B lineages, arising from newly characterized CD117lo multi-lymphoid progenitors (MLPs). Recent data on the lifelong lymphocyte dynamics of healthy donors suggest that, after birth, lymphopoiesis may become increasingly oriented toward the production of B lymphocytes. Stemming from this, we posit that there are three major developmental transitions, the first occurring during the neonatal period, the next at puberty, and the last during aging.