Human immunodeficiency reveals the Zn2+-dependence of B cell development. Human immunodeficiency reveals the Zn2+-dependence of B cell development

Despite the known importance of zinc for human immunity, molecular insights into its roles remain limited. Here we report a novel autosomal recessive disease characterised by early-onset infections, absent B cells and agammaglobulinaemia in five unrelated families. The immunodeficiency results from a series of hypomorphic and null alleles of SLC39A7, which encodes the endoplasmic-reticulum-to-cytoplasm zinc transporter, ZIP7. Using CRISPR-Cas9 editing and homologous recombination we have modelled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic lethality, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited increased phosphatase activity and decreased phosphorylation of signalling molecules that lie downstream of the pre-B and B cell receptors. Our findings highlight a specific role for Zn2+ in modulating B cell receptor signal strength and positive selection, and suggest how Zn2+ could modulate outcome in a variety of signalling contexts. Overall design: We constructed 40 RNA-seq libraries; 4 stages of B cells, 2 conditions (WT and mutant), 5 replicates. 5 WT and 5 P198A/P198A mutant staight chimeras mice were stained and sorted for FrB,C,D,E in BM. 100 cells each sample, processed by Smartseq2. Sequenced by HiSeq4000.