期刊
NATURE IMMUNOLOGY
卷 20, 期 3, 页码 350-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-018-0295-8
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资金
- Medical Research Council [MR/J0003042/1, MR/N00275X/1, MR/L020149/1: DIVA]
- Sir Jules Thorn Trust [12/JTA]
- St Giles Foundation
- Rockefeller University
- INSERM
- Paris Descartes University
- Howard Hughes Medical Institute
- National Institutes of Health [5P01AI061093, 5R01AI104857]
- French National Research Agency [ANR 14-CE15-0009-01]
- Wellcome Trust [WT098424AIA, 090532/Z/09/Z, 207556/Z/17/Z]
- Cancer Research UK [C52690/A19270]
- Diabetes UK [BDA11/0004210, BDA/15/0005275]
- Northern Counties Kidney Research Fund [14.06]
- National Health and Medical Research Council of Australia
- Ludwig Institute for Cancer Research
- BBSRC [BB/J015873/1] Funding Source: UKRI
- MRC [MC_PC_15065, MR/R017549/1, MR/L02036X/1, MR/M012646/1, MR/R010676/1, MR/R007748/1, MR/K001981/1, MC_UU_00008/6, MR/N00275X/1, MR/N020472/1, MR/L001209/1, MR/M009971/1] Funding Source: UKRI
- Medical Research Council [MR/N00275X/1] Funding Source: researchfish
- Wellcome Trust [207556/Z/17/Z] Funding Source: researchfish
- Agence Nationale de la Recherche (ANR) [ANR-14-CE15-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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