ZNT7 binds to CD40 and influences CD154‐triggered p38 MAPK activity in B lymphocytes—a possible regulatory mechanism for zinc in immune function

Abstract

Zinc deficiency impairs the immune system leading to frequent infections. Although zinc is known to play critical roles in maintaining healthy immune function, the underlying molecular targets are largely unknown. In this study, we demonstrate that zinc is important for the CD154–CD40‐mediated activation of downstream signaling pathways in human B lymphocytes. CD40 is a receptor localized on the cell surface of many immune cells, including B lymphocytes. It binds to CD154, a membrane protein expressed on antigen‐activated T helper (Th) lymphocytes. This CD154‐CD40 interaction leads to B‐cell activation. We showed that cellular zinc deficiency impaired the CD154‐CD40‐mediated p38 mitogen‐activated protein kinase (p38 MAPK) phosphorylation. We also showed that zinc supplemental treatment of B lymphocytes had limited effect on this CD40‐mediated p38 MAPK signaling. Most importantly, we demonstrated that the zinc transporter protein zinc transporter 7 (ZNT7) interacted with CD40 using immunoprecipitation analyses. ZNT7 knockdown in B lymphocytes had a negative effect on the cell surface expression of CD40. Consequently, the CD40‐mediated p38 MAPK signaling transduction was down‐regulated in ZNT7KD B lymphocytes. Conversely, this p38 MAPK signaling activity was up‐regulated by overexpression (OE) of ZNT7 in B lymphocytes. Moreover, we found that ZNT7 knockdown in B lymphocytes constitutively up‐ and down‐regulated the inhibitor of i kappa B kinase and AKT serine/threonine kinase phosphorylation, respectively, which implies the activation of survival signaling in ZNT7KD B cells. We conclude that CD40 is the target molecule for ZNT7 in regulation of immune function of B lymphocytes.

Daily Preventive Zinc Supplementation Decreases Lymphocyte and Eosinophil Concentrations in Rural Laotian Children from Communities with a High Prevalence of Zinc Deficiency: Results of a Randomized Controlled Trial

“…Because T-cell concentrations did not decrease in response to zinc treatment, one can speculate that B-cell concentrations did decrease in response to PZ supplementation, but we have no way to assess that retrospectively. Two recent studies have identified 2 different zinc transporters as having key roles in B-cell biology (32,33), suggesting that further examination of this cell type is warranted. Another interpretation of this result is that zinc may have dampened a mild lymphocytosis in this population, perhaps resulting from undiagnosed infections, but this is also speculation.…”

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

“…CD40 is linked to zinc transporter ZnT7 expression in the regulation of immune function of human B lymphocytes. Knockdown of ZnT7 in B lymphocytes decreases expression of CD40 on the cell surface [ 73 ]. Conversely, the A/A genotype, rs430759, of the zinc transporter ZnT6 is associated with a low susceptibility to RA severity, suggesting a protective role of this particular genotype [ 74 ].…”

Supplementation With Zinc Proteinate Increases the Growth Performance by Reducing the Incidence of Diarrhea and Improving the Immune Function of Dairy Calves During the First Month of Life

“…These antibodies recognize and bind to antigens specifically, thereby activating several immune responses (3) that selectively eliminate microorganisms, viruses, and other foreign molecules (31). Zinc deficiency impairs B lymphocyte development and the production of antibodies, especially IgG (32). ZM supplementation reportedly enhanced the resistance to infection by increasing the total immunoglobulin concentration in weaning calves (29).…”