An essential role for the Zn2+ transporter ZIP7 in B cell development

  • Nat Immunol. 2019 Mar;20(3):350-361. doi: 10.1038/s41590-018-0295-8.
Consuelo Anzilotti  1 ,  David J Swan  2 ,  Bertrand Boisson  3  4  5 ,  Mukta Deobagkar-Lele  1 ,  Catarina Oliveira  6 ,  Pauline Chabosseau  7 ,  Karin R Engelhardt  2 ,  Xijin Xu  1 ,  Rui Chen  2 ,  Luis Alvarez  6 ,  Rolando Berlinguer-Palmini  8 ,  Katherine R Bull  1 ,  Eleanor Cawthorne  1 ,  Adam P Cribbs  9 ,  Tanya L Crockford  1 ,  Tarana Singh Dang  2 ,  Amy Fearn  10 ,  Emma J Fenech  11 ,  Sarah J de Jong  3 ,  B Christoffer Lagerholm  1 ,  Cindy S Ma  12  13 ,  David Sims  9 ,  Bert van den Berg  10 ,  Yaobo Xu  14 ,  Andrew J Cant  15 ,  Gary Kleiner  16 ,  T Ronan Leahy  17 ,  M Teresa de la Morena  18 ,  Jennifer M Puck  19  20 ,  Ralph S Shapiro  21 ,  Mirjam van der Burg  22 ,  J Ross Chapman  6 ,  John C Christianson  11 ,  Benjamin Davies  6 ,  John A McGrath  23 ,  Stefan Przyborski  24 ,  Mauro Santibanez Koref  14 ,  Stuart G Tangye  12  13 ,  Andreas Werner  10 ,  Guy A Rutter  7 ,  Sergi Padilla-Parra  6  25  26 ,  Jean-Laurent Casanova  3  4  5  27  28 ,  Richard J Cornall  29 ,  Mary Ellen Conley  30 ,  Sophie Hambleton  31  32
Affiliations
  • 1. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 2. Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 3. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163 Necker Hospital for Sick Children, Paris, France.
  • 5. Paris Descartes University, Imagine Institute, Paris, France.
  • 6. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 7. Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College, London, UK.
  • 8. Bioimaging Unit, Newcastle University Medical School, Newcastle upon Tyne, UK.
  • 9. MRC WIMM Centre for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 10. Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
  • 11. Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • 12. Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 13. St Vincent's Clinical School, Faculty of Medicine, University of NSW, Darlinghurst, New South Wales, Australia.
  • 14. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 15. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 16. Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 17. Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
  • 18. Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
  • 19. Department of Pediatrics, Division of Allergy, Immunology, and Blood and Bone Marrow Transplantation, University of California, San Francisco, CA, USA.
  • 20. UCSF Benioff Children's Hospital, San Francisco, CA, USA.
  • 21. Midwest Immunology Clinic, Plymouth, MN, USA.
  • 22. Department of Immunology, Erasmus University Medical Centre, Rotterdam, the Netherlands.
  • 23. St John's Institute of Dermatology, King's College London, London, UK.
  • 24. Department of Biosciences, Durham University, Durham, UK.
  • 25. Dynamic Structural Virology Group, Biocruces Health Research Institute, Barakaldo, Spain.
  • 26. Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
  • 27. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France.
  • 28. Howard Hughes Medical Institute, New York, NY, USA.
  • 29. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. [email protected].
  • 30. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. [email protected].
  • 31. Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. [email protected].
  • 32. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. [email protected].
PMID: 30718914 DOI: 10.1038/s41590-018-0295-8
Abstract

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased Phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.