IL-7–dependent and –independent lineages of IL-7R–dependent human T cells

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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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-09-30
DOI
https://doi.org/10.1172/jci180251
Citations
5
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
1.20

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article

IL-7–dependent and –independent lineages of IL-7R–dependent human T cells

Julian Rojas, Kathryn Payne, Bénédicte Neven, Luis Alfonso Correa Londoño et al.
5 citations
Journal of Clinical Investigation
Immunodeficiency and Autoimmune Disorders
1.20
article

IL-7–dependent and –independent lineages of IL-7R–dependent human T cells

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

Abstract

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.

Journal of Clinical InvestigationVol. 134(19)
Université Claude Bernard Lyon 1 (FR), Uppsala University (SE), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Howard Hughes Medical Institute (US), Garvan Institute of Medical Research (AU), University of Lisbon (PT), Inserm (FR), Institut Pasteur (FR), Hebrew University of Jerusalem (IL), University of Zurich (CH), Université Paris Cité (FR), Hokkaido University (JP), Hadassah Medical Center (IL), Science for Life Laboratory (SE), University Medical Center Freiburg (DE), Karolinska Institutet (SE), UNSW Sydney (AU), Universidad de Antioquia (CO), Sorbonne Université (FR), Hospital Universitario del Valle ESE (CO), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Institute of Agrifood Research and Technology (ES), Laboratoire Chrono-Environnement (FR), Immunité et Cancer (FR), Assaf Harofeh Medical Center (IL), Clínica Santa María (CO), National Institute of Allergy and Infectious Diseases (US), Institut Cochin (FR), Hôpital Saint-Louis (FR), Hamad bin Khalifa University (QA), Hôpital Bichat-Claude-Bernard (FR), Physiopathologie et Epidémiologie des Maladies Respiratoires (FR), Institut de Génétique Humaine (FR), Institut des Maladies Génétiques Imagine (FR), Hôpital Tenon (FR), Rockefeller University (US), Université de Franche-Comté (FR), Universidad del Valle (CO)
“la Caixa” Foundation, Agence Nationale de la Recherche, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Zero hunger
Openalex Percentile: Top 21%
Immunodeficiency and Autoimmune Disorders
1.20
DOIOpen Access PDFOpenAlex
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