An essential role for the Zn2+ transporter ZIP7 in B cell development.
Nat Immunol
; 20(3): 350-361, 2019 03.
Article
in En
| MEDLINE
| ID: mdl-30718914
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Zinc
/
B-Lymphocytes
/
Cation Transport Proteins
/
Agammaglobulinemia
Type of study:
Prognostic_studies
Limits:
Animals
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
Language:
En
Journal:
Nat Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Reino Unido