Study Title:

Zinc and Immunity

Study Abstract

The zinc transporter ZIP8 is highly expressed in T cells derived from human subjects. T cell ZIP8 expression was markedly up-regulated upon in vitro activation. T cells collected from human subjects who had received oral zinc supplementation (15 mg/day) had higher expression of the activation marker IFN- upon in vitro activation, indicating a potentiating effect of zinc on T cell activation. Similarly, in vitro zinc treatment of T cells along with activation resulted in increased IFN- expression with a maximum effect at 3.1 µM. Knockdown of ZIP8 in T cells by siRNA decreased ZIP8 levels in nonactivated and activated cells and concomitantly reduced secretion of IFN- and perforin, both signatures of activation. Overexpression of ZIP8 by transient transfection caused T cells to exhibit enhanced activation. Confocal microscopy established that ZIP8 is localized to the lysosome where ZIP8 abundance is increased upon activation. Loss of lysosomal labile zinc in response to activation was measured by flow cytometry using a zinc fluorophore. Zinc between 0.8 and 3.1 µM reduced CN phosphatase activity. CN was also inhibited by the CN inhibitor FK506 and ZIP8 overexpression. The results suggest that zinc at low concentrations, through inhibition of CN, sustains phosphorylation of the transcription factor CREB, yielding greater IFN- expression in T cells. ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN- regulation in T cells.

From press release:

Everyone knows that vitamins "from A to zinc" are important for good health. Now, a new research study in the August 2009 print issue of the Journal of Leukocyte Biology suggests that zinc may be pointing the way to new therapeutic targets for fighting infections. Specifically, scientists from Florida found that zinc not only supports healthy immune function, but increases activation of the cells (T cells) responsible for destroying viruses and bacteria.

"It has been shown that zinc supplementation significantly reduces the duration and severity of childhood diarrhea, lower respiratory infections, and incidence of malaria in zinc-deficient children," said report co-author, Robert Cousins, Ph.D., who also is the director of the Center for Nutritional Sciences within the Food Science and Human Nutrition Department at the University of Florida. "Age-related declines in immune function have also been related to zinc deficiency in the elderly."

Scientists administered either a zinc supplement or a placebo to healthy volunteers to assess the effects of zinc on T cell activation. After isolating the T cells from the blood, scientists then simulated infection in laboratory conditions. Results showed that T cells taken from the zinc-supplemented group had higher activation than those from the placebo group. Specifically, cell activation stimulated the zinc transporter in T cells called "ZIP8," which transports stored zinc into the cell cytoplasm where it then alters the expression of a T cell protein in a way needed to fight infections.

"As the debate over zinc supplementation in healthy individuals continues," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, "studies like this help shed light on how zinc may enhance the ability of our immune systems to fight off foreign invaders. Equally important, this work points toward new possible targets for entirely new drugs to help augment immune function and prevent or stop infections that might be resistant to traditional antibiotics."

Study Information

Tolunay B. Aydemir, Juan P. Liuzzi, Steve McClellan, and Robert J. Cousins.
Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN- expression in activated human T cells.
Journal of Leukocyte Biology.
2009 August
Center for Nutritional Sciences, College of Agricultural and Life Sciences,Department of Biochemistry and Molecular Biology, College of Medicine, andInterdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, Florida, USA.

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