The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants
Marie Materna(Inserm), Ottavia M. Delmonte(National Institutes of Health), Marita Bosticardo(National Institutes of Health), Mana Momenilandi(Inserm), Peyton Conrey(Children's Hospital of Philadelphia), Bénédicte Charmeteau-De Muylder(Centre National de la Recherche Scientifique), Clotilde Bravetti(Institut de la Vision), Rebecca Bellworthy(McGill Genome Centre), Axel Cederholm(Uppsala University), Frederik Staels(KU Leuven), Christian A. Ganoza(Centogene (Germany)), Samuel Darko(National Institutes of Health), Samir Sayed(Children's Hospital of Philadelphia), Corentin Le Floc’h(Inserm), Masato Ogishi(Rockefeller University), Darawan Rinchai(Rockefeller University), Andrea Guenoun, Alexandre Bolze(Helix (United States)), Taushif Khan(Jackson Laboratory), Adrian Gervais(Inserm), Renate Krüger(Humboldt-Universität zu Berlin), Mirjam Völler(Humboldt-Universität zu Berlin), Boaz Palterer(National Institutes of Health), Mahnaz Sadeghi‐Shabestari(Tabriz University of Medical Sciences), Anne Langlois de Septenville(Sorbonne Université), Chaim A. Schramm(National Institutes of Health), Sanjana Shah(National Institutes of Health), John James Tello Cajiao(Children's Hospital of Philadelphia), Francesca Pala(National Institutes of Health), Kayla Amini(National Institutes of Health), Jose Campos(Children's Hospital of Philadelphia), Noemia S. Lima(National Institutes of Health), Daniel Eriksson(Uppsala University Hospital), Romain Lévy(Inserm), Yoann Seeleuthner(Inserm), Soma Jyonouchi(Children's Hospital of Philadelphia), Manar Ata, Fatima Al Ali, Caroline Deswarte(Inserm), A B Pereira(Inserm), Jérôme Megret(Centre National de la Recherche Scientifique), Tom Le Voyer(Inserm), Paul Bastard(Inserm), Laureline Berteloot(Hôpital Necker-Enfants Malades), Michaël Dussiot(Inserm), Natasha Vladikine(Inserm), Paula P. Cárdenas(Research Institute Hospital 12 de Octubre), Emmanuelle Jouanguy(Inserm), Mashael Alqahtani(King Faisal Specialist Hospital & Research Centre), Amal Hasan(Dasman Diabetes Institute), Thangavel Alphonse Thanaraj(Dasman Diabetes Institute), Jérémie Rosain(Inserm), Fahd Al Qureshah(Rockefeller University), Vito Sabato(University of Antwerp), Marie Alexandra Alyanakian(Assistance Publique – Hôpitaux de Paris), Marianne Leruez‐Ville(Hôpital Necker-Enfants Malades), Flore Rozenberg(Centre National de la Recherche Scientifique), Élie Haddad(Centre Hospitalier Universitaire Sainte-Justine), José R. Regueiro(Research Institute Hospital 12 de Octubre), Marı́a L. Toribio(Centro de Biología Molecular Severo Ochoa), Judith R. Kelsen(Children's Hospital of Philadelphia), Mansoor Salehi(Isfahan University of Medical Sciences), Shahram Nasiri(Ahvaz Jundishapur University of Medical Sciences), Mehdi Torabizadeh(Ahvaz Jundishapur University of Medical Sciences), Hassan Rokni‐Zadeh(Zanjan University of Medical Sciences), Majid Changi‐Ashtiani(Institute for Research in Fundamental Sciences), Nasimeh Vatandoost(Isfahan University of Medical Sciences), Hossein Moravej(Shiraz University of Medical Sciences), Seyed Mohammad Akrami(Shahed University), Mohsen Mazloomrezaei(Shahed University), Aurélie Cobat(Inserm), Isabelle Meyts(KU Leuven), Etsushi Toyofuku(Tokyo Medical and Dental University), Madoka Nishimura(Kumamoto Medical Center), Kunihiko Moriya(National Defense Medical College), Tomoyuki Mizukami(Kumamoto Medical Center), Kohsuke Imai(National Defense Medical College), Laurent Abel(Inserm), Bernard MALISSEN(Centre National de la Recherche Scientifique), Fahd Al‐Mulla(Dasman Diabetes Institute), Fowzan S. Alkuraya(Alfaisal University), Nima Parvaneh(Tehran University of Medical Sciences), Horst von Bernuth(Humboldt-Universität zu Berlin), Christian Beetz(Centogene (Germany)), Frédéric Davi(Institut de la Vision), Daniel C. Douek(National Institutes of Health), Rémi Cheynier(Centre National de la Recherche Scientifique), David Langlais(McGill Genome Centre), Nils Landegren(Uppsala University), Nico Marr(Hamad bin Khalifa University), Tomohiro Morio(Tokyo Medical and Dental University), Mohammad Shahrooei(Shahed University), Rik Schrijvers(KU Leuven), Sarah E. Henrickson(Children's Hospital of Philadelphia), Hervé Luche(Centre National de la Recherche Scientifique), Luigi D. Notarangelo(National Institutes of Health), Jean‐Laurent Casanova(Howard Hughes Medical Institute), Vivien Béziat(Inserm)
Cited by 37Open Access
Abstract
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre–α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.
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