title: Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations.
abstract: Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell-intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+T cells are reduced. Their CD4+T cells do not respond to CD28 stimulation. Their CD4+T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients' B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Yi
authors.identifier: 0000-0002-1985-3404
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca 20100, Morocco.
authors.forename: Aziz
authors.initials: A
authors.lastname: Bousfiha
authors.affiliation: Division of Infectious Diseases, Clinical Immunology, and Allergy, Department of Pediatrics, Cerrahpaşa Medical Faculty, Istanbul University, 34452 Istanbul, Turkey.
authors.forename: Yildiz
authors.identifier: 0000-0002-4796-6828
authors.initials: Y
authors.lastname: Camcioglu
authors.affiliation: Immunology Unit, Rouen University Hospital, 76031 Rouen, France.|Institut National de la Santé et de la Recherche Médicale U905, Institute for Research and Innovation in Biomedicine, Rouen Normandy University, 76183 Rouen, France.
authors.forename: Serge
authors.identifier: 0000-0002-9017-8368
authors.initials: S
authors.lastname: Jacquot
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Kathryn
authors.identifier: 0000-0003-3311-5210
authors.initials: K
authors.lastname: Payne
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Elena
authors.initials: E
authors.lastname: Crestani
authors.affiliation: Center for Immunology Marseille-Luminy, 13288 Marseille, France.
authors.forename: Romain
authors.identifier: 0000-0001-7554-0552
authors.initials: R
authors.lastname: Roncagalli
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Aziz
authors.identifier: 0000-0002-8488-9737
authors.initials: A
authors.lastname: Belkadi
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Gaspard
authors.identifier: 0000-0003-0146-9428
authors.initials: G
authors.lastname: Kerner
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Lazaro
authors.identifier: 0000-0001-6648-8684
authors.initials: L
authors.lastname: Lorenzo
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Deswarte
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.affiliation: Human Evolutionary Genetics Unit, Institut Pasteur, 75015 Paris, France.|Centre National de la Recherche Scientifique URA 3012, 75015 Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Patin
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Quentin B
authors.initials: QB
authors.lastname: Vincent
authors.affiliation: Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Müller-Fleckenstein
authors.affiliation: Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors.forename: Bernhard
authors.identifier: 0000-0002-4687-469X
authors.initials: B
authors.lastname: Fleckenstein
authors.affiliation: Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca 20100, Morocco.
authors.forename: Fatima
authors.identifier: 0000-0001-5824-3193
authors.initials: F
authors.lastname: Ailal
authors.affiliation: Human Evolutionary Genetics Unit, Institut Pasteur, 75015 Paris, France.|Centre National de la Recherche Scientifique URA 3012, 75015 Paris, France.
authors.forename: Lluis
authors.initials: L
authors.lastname: Quintana-Murci
authors.affiliation: Department of Pathology, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fraitag
authors.affiliation: Immunology Unit, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Marie-Alexandra
authors.initials: MA
authors.lastname: Alyanakian
authors.affiliation: Virology Laboratory, Paris Descartes University, Sorbonne Paris Cité-EA 36-20, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Leruez-Ville
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.|Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Anne
authors.identifier: 0000-0003-2603-0323
authors.initials: A
authors.lastname: Puel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.|Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.affiliation: Center for Immunology Marseille-Luminy, 13288 Marseille, France.
authors.forename: Marie
authors.identifier: 0000-0003-2331-1445
authors.initials: M
authors.lastname: Malissen
authors.affiliation: Center for Immunology Marseille-Luminy, 13288 Marseille, France.
authors.forename: Bernard
authors.identifier: 0000-0003-1340-9342
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Laurent
authors.identifier: 0000-0001-7016-6493
authors.initials: L
authors.lastname: Abel
authors.affiliation: Laboratory of Genetic Skin Diseases: from Disease Mechanism to Therapies, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
authors.forename: Luigi D
authors.identifier: 0000-0002-8335-0262
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.|St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Stuart G
authors.identifier: 0000-0002-5360-5180
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France vivien.beziat@inserm.fr.|Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Vivien
authors.identifier: 0000-0002-4020-824X
authors.initials: V
authors.lastname: Béziat
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.|Paris Descartes University, Imagine Institute, 75015 Paris, France.|Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.|St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.|Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.
authors.forename: Jean-Laurent
authors.identifier: 0000-0002-7782-4169
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019281:Dimerization; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D007962:Leukocytes / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D011947:Receptors, Antigen, B-Cell; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D055815:Young Adult
chemical_list: C547525:CARMIL1 protein, human; D018106:CD28 Antigens; D008840:Microfilament Proteins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell