IL-7–dependent and –independent lineages of IL-7R–dependent human T cells
Carlos A. Arango-Franco, et al.
Carlos A. Arango-Franco, et al.
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Research Article Genetics Immunology

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

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

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Figure 7

Peripheral T cell functions.

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Peripheral T cell functions. (A and B) Fresh PBMCs from age-matched cont...
(A and B) Fresh PBMCs from age-matched controls (only 2 controls are shown), P1, and P2 were incubated for 4 days with (A) PHA (5 μg/mL or 20 μg/mL), or (B) with beads coated with anti-CD3 and anti-CD28 mAbs (anti-CD3 mAbs were used at concentrations of 1.25 μg/mL and 5 μg/mL). Histograms show CFSE dilution for CD3+ T lymphocytes. Representative results from 2 independent experiments are shown. (C) Intracellular IL-2 production by CD4+ or CD8+ naive or memory T cells after stimulation with PMA plus ionomycin for 4 hours and flow cytometry analysis, for IL-7–deficient patients (P4, P5, and P6) and 3 healthy controls. (D and E) Memory CD4+ T cells from healthy controls, P1, and P2 were stimulated with PMA plus ionomycin after 5 days of culture; the percentages of cells expressing IFN-γ, TNF, IL-2, and IL-10 intracellularly were determined by flow cytometry (D) and secreted cytokines were assessed by LEGENDplex (E). (F) T cell blasts from P1–P3 and 3 healthy controls were stimulated for 2 hours with an anti-CD2/anti-CD3/anti-CD28 mAb cocktail. Secreted cytokines were determined by LEGENDplex. (G and H) Bulk RNA transcriptomic analysis on sorted CD4+ and CD8+ T cell blasts from P1–P3 and 3 healthy adult controls. Principal component analysis (PCA) results are shown for sorted CD4+ and CD8+ T cell blasts in the absence of stimulation or after stimulation with the anti-CD2/anti-CD3/anti-CD28 mAb cocktail (G). Normalized enrichment score (NES) analyses are shown for unstimulated sorted CD4+ and CD8+ T cell blasts (H).