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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / immunology*
  • Cell Differentiation / immunology
  • Cellular Senescence / immunology
  • Immunity, Humoral*
  • Leukocyte Common Antigens / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • Zinc / metabolism*

Substances

  • Cation Transport Proteins
  • Receptors, Antigen, B-Cell
  • ZIP10 protein, mouse
  • Leukocyte Common Antigens
  • Zinc