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

• Text
• PDF

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.

Authors

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