Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance

J Exp Med. 2019 Jun 3;216(6):1311-1327. doi: 10.1084/jem.20182304.

Zinan Zhang ^# ¹ ² ³, Florian Gothe ^# ⁴ ⁵, Perrine Pennamen ^# ⁶, John R James ⁷, David McDonald ⁴, Carlos P Mata ¹ ⁷, Yorgo Modis ¹ ⁷, Anas M Alazami ⁸, Meghan Acres ⁴, Wolfram Haller ⁹, Claire Bowen ⁹, Rainer Döffinger ¹⁰, Jan Sinclair ¹¹, Shannon Brothers ¹¹, Yu Zhang ², Helen F Matthews ², Sophie Naudion ⁶, Fanny Pelluard ¹², Huda Alajlan ⁸, Yasuhiro Yamazaki ¹³, Luigi D Notarangelo ¹³, James E Thaventhiran ¹, Karin R Engelhardt ⁴, Hamoud Al-Mousa ¹⁴, Sophie Hambleton ^# ¹⁵ ¹⁶, Caroline Rooryck ^# ⁶, Kenneth G C Smith ^# ¹⁷, Michael J Lenardo ^# ¹⁸

Affiliations

1 Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK.
2 Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
3 Harvard Medical School, Boston, MA.
4 Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
5 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
6 University of Bordeaux, Maladies Rares: Génétique et Métabolisme Institut National de la Santé et de la Recherche Médicale U1211, Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Médicale, Bordeaux, France.
7 Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK.
8 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
9 Birmingham Children's Hospital, Birmingham, UK.
10 Department of Clinical Biochemistry and Immunology, Cambridge University Hospital, Cambridge, UK.
11 Starship Children's Hospital, Auckland, New Zealand.
12 Department of Pathology, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France.
13 Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
14 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
15 Institute of Cellular Medicine, Newcastle University, Newcastle, UK [email protected].
16 Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle, UK.
17 Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK [email protected].
18 Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD [email protected].
# Contributed equally.

PMID: 31040185 DOI: 10.1084/jem.20182304

Abstract

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and Cancer.

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