FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice
Mana Momenilandi, Romain Lévy, Steicy Sobrino, Jingwei Li, Chantal Lagresle‐Peyrou, Hossein Esmaeilzadeh, Antoine Fayand, Corentin Le Floc’h, Antoine Guérin, Erika Della Mina, Debra A. Shearer, Ottavia M. Delmonte, Ahmad Yatim, Kevin Mulder, Mathieu Mancini, Darawan Rinchai, Adeline Denis, Anna‐Lena Neehus, Karla K. Balogh, Sarah A. Brendle, Hassan Rokni‐Zadeh, Majid Changi‐Ashtiani, Yoann Seeleuthner, Caroline Deswarte, Boris Bessot, Cassandre Crémadès, Marie Materna, Axel Cederholm, Masato Ogishi, Quentin Philippot, Omer Beganovic, Mania Ackermann, Margareta Wuyts, Taushif Khan, S. Fouéré, F. Herms, J. Chanal, Boaz Palterer, Julie Bruneau, Thierry Jo Molina, Stéphanie Leclerc‐Mercier, Jean‐Luc Prétet, Leila Youssefian, Hassan Vahidnezhad, Nima Parvaneh, Kristl G. Claeys, Rik Schrijvers, Marine Luka, Philippe Pérot, Jacques Fourgeaud, Céline Nourrisson, Philippe Poirier, Emmanuelle Jouanguy, Stéphanie Boisson‐Dupuis, Jacinta Bustamante, Luigi D. Notarangelo, Neil D. Christensen, Nils Landegren, Laurent Abel, Nico Marr, Emmanuelle Six, David Langlais, Tim Waterboer, Florent Ginhoux, S. Cindy, Stuart G. Tangye, Isabelle Meyts, Nico Lachmann, Jiafen Hu, Mohammad Shahrooei, Xavier Bossuyt, Jean‐Laurent Casanova, Vivien Béziat
Abstract
FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.