IL-7-dependent and -Independent Lineages of IL-7R-dependent Human T Cells

Carlos A Arango-Franco,Masato Ogishi,Susanne Unger,Ottavia M Delmonte,Julio César Orrego,Ahmad Yatim, Margarita M Velasquez-Lopera, Andrés F Zea-Vera,Jonathan Bohlen,Marwa Chbihi,Antoine Fayand, Juan Pablo Sánchez, Julian Rojas,Yoann Seeleuthner,Tom Le Voyer, Quentin Philippot,Kathryn J Payne,Adrian Gervais, Lucia V Erazo-Borrás, Luis A Correa-Londoño,Axel Cederholm, Alejandro Gallón-Duque,Pedro Goncalves,Jean-Marc Doisne, Liran Horev,Bénédicte Charmeteau-de Muylder, Jesús Á Álvarez, Diana M Arboleda, Lizet Pérez-Zapata, Estefanía Vásquez-Echeverri,Marcela Moncada-Vélez, Juan A López, Yolanda Caicedo,Boaz Palterer,Pablo J Patiño, Carlos J Montoya, Matthieu Chaldebas,Peng Zhang,Tina Nguyen, Cindy S Ma,Mohamed Jeljeli, Juan F Alzate,Felipe Cabarcas,Taushif Khan,Darawan Rinchai, Jean-Luc Prétet, Bertrand Boisson, Generalized Verrucosis Japanese Consortium,Nico Marr, Ruba Ibrahim,Vered Molho-Pessach,Stéphanie Boisson-Dupuis,Dimitra Kiritsi, João T Barata,Nils Landegren, Bénédicte Neven,Laurent Abel,Andrea Lisco, Vivien Béziat,Emmanuelle Jouanguy, Jacinta Bustamante,James P Di Santo,Stuart G Tangye, Luigi D Notarangelo, Rémi Cheynier, Ken Natsuga,Andrés A Arias, José Luis Franco, Klaus Warnatz,Jean-Laurent Casanova, Anne Puel

The Journal of clinical investigation(2024)

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摘要
Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.
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