The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants

• 成果类型: Article
• 署名作者: Materna, Marie; Delmonte, Ottavia M.; Bosticardo, Marita; Momenilandi, Mana; Conrey, Peyton E.; Charmeteau-De Muylder, Benedicte; Bravetti, Clotilde; Bellworthy, Rebecca; Cederholm, Axel; Staels, Frederik; Ganoza, Christian A.; Darko, Samuel; Sayed, Samir; Le Floc'h, Corentin; Ogishi, Masato; Rinchai, Darawan; Guenoun, Andrea; Bolze, Alexandre; Khan, Taushif; Gervais, Adrian; Krueger, Renate; Voeller, Mirjam; Palterer, Boaz; Sadeghi-Shabestari, Mahnaz; de Septenville, Anne Langlois; Schramm, Chaim A.; Shah, Sanjana; Tello-Cajiao, John J.; Pala, Francesca; Amini, Kayla; Campos, Jose S.; Lima, Noemia Santana; Eriksson, Daniel; Levy, Romain; Seeleuthner, Yoann; Jyonouchi, Soma; Ata, Manar; Al Ali, Fatima; Deswarte, Caroline; Pereira, Anais; Megret, Jerome; Le Voyer, Tom; Bastard, Paul; Berteloot, Laureline; Dussiot, Michael; Vladikine, Natasha; Cardenas, Paula P.; Jouanguy, Emmanuelle; Alqahtani, Mashael; Hasan, Amal; Thanaraj, Thangavel Alphonse; Rosain, Jeremie; Al Qureshah, Fahd; Sabato, Vito; Alyanakian, Marie Alexandra; Leruez-Ville, Marianne; Rozenberg, Flore; Haddad, Elie; Regueiro, Jose R.; Toribio, Maria L.; Kelsen, Judith R.; Salehi, Mansoor; Nasiri, Shahram; Torabizadeh, Mehdi; Rokni-Zadeh, Hassan; Changi-Ashtiani, Majid; Vatandoost, Nasimeh; Moravej, Hossein; Akrami, Seyed Mohammad; Mazloomrezaei, Mohsen; Cobat, Aurelie; Meyts, Isabelle; Toyofuku, Etsushi; Nishimura, Madoka; Moriya, Kunihiko; Mizukami, Tomoyuki; Imai, Kohsuke; Abel, Laurent; Malissen, Bernard; Al-Mulla, Fahd; Alkuraya, Fowzan Sami; Parvaneh, Nima; von Bernuth, Horst; Beetz, Christian; Davi, Frederic; Douek, Daniel C.; Cheynier, Remi; Langlais, David; Landegren, Nils; Marr, Nico; Morio, Tomohiro; Shahrooei, Mohammad; Schrijvers, Rik; Henrickson, Sarah E.; Luche, Herve; Notarangelo, Luigi D.; Casanova, Jean-Laurent; Beziat, Vivien
• 署名单位: Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Sorbonne Universite; Sorbonne Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Sorbonne Universite; McGill University; Uppsala University; KU Leuven; CENTOGENE AG; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Rockefeller University; Sidra Medical & Research Center; Jackson Laboratory; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Tabriz University of Medical Science; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Uppsala University; Uppsala University; Uppsala University Hospital; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Centre National de la Recherche Scientifique (CNRS); Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Complutense University of Madrid; King Faisal Specialist Hospital & Research Center; Dasman Diabetes Institute (DDI); Dasman Diabetes Institute (DDI); University of Antwerp; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Cochin - APHP; Universite de Montreal; Centre Hospitalier Universitaire Sainte-Justine; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de Biologia Molecular Severo Ochoa (CBM); Autonomous University of Madrid; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Isfahan University of Medical Sciences; Isfahan University of Medical Sciences; Ahvaz Jundishapur University of Medical Sciences (AJUMS); Ahvaz Jundishapur University of Medical Sciences (AJUMS); Institute for Research in Fundamental Sciences IPM; Isfahan University of Medical Sciences; Shiraz University of Medical Science; Tehran University of Medical Sciences; KU Leuven; University Hospital Leuven; KU Leuven; University Hospital Leuven; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); National Defense Medical College - Japan; Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Alfaisal University; Tehran University of Medical Sciences; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Karolinska Institutet; Qatar Foundation (QF); Hamad Bin Khalifa University-Qatar; KU Leuven; University of Pennsylvania; University of Pennsylvania; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Howard Hughes Medical Institute; Rockefeller University; Saint Marianna University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8560
• DOI: 10.1126/science.adh4059
• 发表日期: 2024-03-01
• 关键词: t-cell-receptor; gamma-delta; gene rearrangement; allelic exclusion; beta; expression; chain; thymocytes; autoantibodies; repertoire

摘要

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-alpha T cell receptor (pre-TCR alpha) expression. Low circulating naive alpha beta T cell counts at birth persisted over time, with normal memory alpha beta and high gamma delta T cell counts. Their TCR alpha repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue alpha beta 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 alpha beta T cell counts but high gamma delta T cell counts. Although residual pre-TCR alpha expression drove the differentiation of more alpha beta T cells, autoimmune conditions were more frequent in these patients compared with the general population.