Multimodal cartography of human lymphopoiesis reveals B and T/NK/ILC lineages are subjected to differential regulation
Kutaiba Alhaj Hussen,
Emna Chabaane,
Elisabeth Nelson,
Shalva Lekiashvili,
Samuel Diop,
Seydou Keita,
Bertrand Evrard,
Aurélie Lardenois,
Marc Delord,
Els Verhoeyen,
Kerstin Cornils,
Zeinab Kasraian,
Elizabeth A. Macintyre,
Ana Cumano,
David Garrick,
Michele Goodhardt,
Guillaume P. Andrieu,
Vahid Asnafi,
Frederic Chalmel,
Bruno Canque
Affiliations
Kutaiba Alhaj Hussen
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France; Service de Biochimie, Université de Paris Saclay, Hôpital Paul Brousse, AP-HP, Villejuif, Paris, France
Emna Chabaane
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Elisabeth Nelson
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Shalva Lekiashvili
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Samuel Diop
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Seydou Keita
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Bertrand Evrard
University Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
Aurélie Lardenois
University Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
Marc Delord
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Els Verhoeyen
CIRI, International Center for Infectiology Research, Université de Lyon, INSERM U1111, Lyon, France; Centre Mediterranéen de Médecine Moléculaire (C3M), INSERM U1065, Nice, France
Kerstin Cornils
Division of Pediatric Stem Cell Transplantation and Immunology, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf and Research Institute Children’s Cancer Center, Hamburg, Germany
Zeinab Kasraian
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France; Institut Necker Enfants-Malades, INSERM U1151, Hôpital Necker Enfants-Malades, Laboratoire d'Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
Elizabeth A. Macintyre
Institut Necker Enfants-Malades, INSERM U1151, Hôpital Necker Enfants-Malades, Laboratoire d'Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
Ana Cumano
Unit of Lymphopoiesis, Immunology Department, Institut Pasteur, Paris, France
David Garrick
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Michele Goodhardt
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France
Guillaume P. Andrieu
Institut Necker Enfants-Malades, INSERM U1151, Hôpital Necker Enfants-Malades, Laboratoire d'Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
Vahid Asnafi
Institut Necker Enfants-Malades, INSERM U1151, Hôpital Necker Enfants-Malades, Laboratoire d'Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
Frederic Chalmel
University Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000 Rennes, France
Bruno Canque
INSERM U976, Université de Paris, École Pratique des Hautes Études/PSL Research University, Institut de Recherche Saint Louis, Paris, France; Corresponding author
Summary: The developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map demonstrating that lymphoid specification follows independent direct or stepwise hierarchic routes converging toward the emergence of newly characterized CD117lo multi-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127- (NK/ILC/T) or CD127+ (B) lymphoid pathways. While the differentiation of CD127- early lymphoid progenitors is mainly driven by Flt3 signaling, emergence of their CD127+ counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their upstream precursors, including hematopoietic stem cells. Further, transcriptional mapping of differentiation trajectories reveals that whereas myeloid granulomonocytic lineages follow continuous differentiation pathways, lymphoid trajectories are intrinsically discontinuous and characterized by sequential waves of cell proliferation allowing pre-commitment amplification of lymphoid progenitor pools. Besides identifying new lymphoid specification pathways and regulatory checkpoints, our results demonstrate that NK/ILC/T and B lineages are under fundamentally distinct modes of regulation. (149 words)
