Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations

J Exp Med. 2016 Oct 17;213(11):2413-2435. doi: 10.1084/jem.20160576.

Yi Wang ¹ ², Cindy S Ma ³ ⁴, Yun Ling ¹ ², Aziz Bousfiha ⁵, Yildiz Camcioglu ⁶, Serge Jacquot ⁷ ⁸, Kathryn Payne ³, Elena Crestani ⁹, Romain Roncagalli ¹⁰, Aziz Belkadi ¹ ², Gaspard Kerner ¹ ², Lazaro Lorenzo ¹ ², Caroline Deswarte ¹ ², Maya Chrabieh ¹ ², Etienne Patin ¹¹ ¹², Quentin B Vincent ¹ ², Ingrid Müller-Fleckenstein ¹³, Bernhard Fleckenstein ¹³, Fatima Ailal ⁵, Lluis Quintana-Murci ¹¹ ¹², Sylvie Fraitag ¹⁴, Marie-Alexandra Alyanakian ¹⁵, Marianne Leruez-Ville ¹⁶, Capucine Picard ¹ ² ¹⁷, Anne Puel ¹ ², Jacinta Bustamante ¹ ² ¹⁷, Stéphanie Boisson-Dupuis ¹ ² ¹⁸, Marie Malissen ¹⁰, Bernard Malissen ¹⁰, Laurent Abel ¹ ², Alain Hovnanian ¹⁹ ², Luigi D Notarangelo ⁹ ²⁰, Emmanuelle Jouanguy ¹ ² ¹⁸, Stuart G Tangye ³ ⁴, Vivien Béziat ²¹ ², Jean-Laurent Casanova ¹ ² ²² ¹⁸ ²³

Affiliations

1 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.
2 Paris Descartes University, Imagine Institute, 75015 Paris, France.
3 Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
4 St. Vincent's Clinical School, University of New South Wales, Darlinghurst, Sydney, NSW 2010, Australia.
5 Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca 20100, Morocco.
6 Division of Infectious Diseases, Clinical Immunology, and Allergy, Department of Pediatrics, Cerrahpaşa Medical Faculty, Istanbul University, 34452 Istanbul, Turkey.
7 Immunology Unit, Rouen University Hospital, 76031 Rouen, France.
8 Institut National de la Santé et de la Recherche Médicale U905, Institute for Research and Innovation in Biomedicine, Rouen Normandy University, 76183 Rouen, France.
9 Division of Immunology, Boston Children's Hospital, Boston, MA 02115.
10 Center for Immunology Marseille-Luminy, 13288 Marseille, France.
11 Human Evolutionary Genetics Unit, Institut Pasteur, 75015 Paris, France.
12 Centre National de la Recherche Scientifique URA 3012, 75015 Paris, France.
13 Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
14 Department of Pathology, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
15 Immunology Unit, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
16 Virology Laboratory, Paris Descartes University, Sorbonne Paris Cité-EA 36-20, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
17 Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
18 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
19 Laboratory of Genetic Skin Diseases: from Disease Mechanism to Therapies, Institut National de la Santé et de la Recherche Médicale U1163, 75015 Paris, France.
20 Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.
21 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.
22 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
23 Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.

PMID: 27647349 DOI: 10.1084/jem.20160576

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.

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