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Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11786-91. doi: 10.1073/pnas.1323557111. Epub 2014 Jul 29.

Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength.

Author information

1
Laboratory for Homeostatic Network,Osteoimmunology, Deutsches Rheuma-Forschungszentrum, 10117 Berlin, Germany;
2
Laboratory for Immune Regeneration,Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan;
3
Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan;
4
Laboratory for Immunotherapy.
5
Laboratory for Immunogenetics.
6
Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan;
7
Bioscience Research Institute, Amorepacific Corporation Research and Development Center, Yongin 446-729, Republic of Korea;Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan;
8
Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan;
9
Molecular Neuroimmunology, Institute of Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan; and.
10
Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.
11
Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, JapanLaboratory for Integrative Genomics, and.
12
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan;
13
Laboratory for Immune Regeneration.
14
Laboratory for Homeostatic Network,Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan; fukada@rcai.riken.jp.

Abstract

The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell-dependent and -independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.

KEYWORDS:

B lymphocyte; acquired immunity; antigen-presenting cell; germinal center; zinc signaling

PMID:
25074919
PMCID:
PMC4136588
DOI:
10.1073/pnas.1323557111
[Indexed for MEDLINE]
Free PMC Article

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