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Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery

Natalia Colomar-Carando, Alberto Meseguer, Iván Company-Garrido, Sabrina Jutz, Víctor Herrera-Fernández, Alex Olvera, Kerstin Kiefer, Christian Brander, Peter Steinberger and Rubén Vicente
J Immunol December 14, 2018, ji1800689; DOI: https://doi.org/10.4049/jimmunol.1800689
Natalia Colomar-Carando
*Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain;
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Alberto Meseguer
*Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain;
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Iván Company-Garrido
*Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain;
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Sabrina Jutz
†Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
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Víctor Herrera-Fernández
*Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain;
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Alex Olvera
‡HIVACAT, IrsiCaixa AIDS Research Institute, Germans Trias i Pujol University Hospital, 08916 Badalona, Spain;
§University of Vic and Central Catalonia, 08500 Vic, Spain; and
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Kerstin Kiefer
*Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain;
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Christian Brander
‡HIVACAT, IrsiCaixa AIDS Research Institute, Germans Trias i Pujol University Hospital, 08916 Badalona, Spain;
§University of Vic and Central Catalonia, 08500 Vic, Spain; and
¶Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain
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Peter Steinberger
†Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria;
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Rubén Vicente
*Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain;
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Abstract

Zinc deficiency causes immune dysfunction. In T lymphocytes, hypozincemia promotes thymus atrophy, polarization imbalance, and altered cytokine production. Zinc supplementation is commonly used to boost immune function to prevent infectious diseases in at-risk populations. However, the molecular players involved in zinc homeostasis in lymphocytes are poorly understood. In this paper, we wanted to determine the identity of the transporter responsible for zinc entry into lymphocytes. First, in human Jurkat cells, we characterized the effect of zinc on proliferation and activation and found that zinc supplementation enhances activation when T lymphocytes are stimulated using anti-CD3/anti-CD28 Abs. We show that zinc entry depends on specific pathways to correctly tune the NFAT, NF-κB, and AP-1 activation cascades. Second, we used various human and murine models to characterize the zinc transporter family, Zip, during T cell activation and found that Zip6 was strongly upregulated early during activation. Therefore, we generated a Jurkat Zip6 knockout (KO) line to study how the absence of this transporter affects lymphocyte physiology. We found that although Zip6KO cells showed no altered zinc transport or proliferation under basal conditions, under activation, these KO cells showed deficient zinc transport and a drastically impaired activation program. Our work shows that zinc entry into activated lymphocytes depends on Zip6 and that this transporter is essential for the correct function of the cellular activation machinery.

Footnotes

  • This work was supported by a grant from the Spanish Ministry of Economy and Competitiveness (SAF2014-52228-R).

  • The online version of this article contains supplemental material.

  • Received May 14, 2018.
  • Accepted November 13, 2018.
  • Copyright © 2018 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery
Natalia Colomar-Carando, Alberto Meseguer, Iván Company-Garrido, Sabrina Jutz, Víctor Herrera-Fernández, Alex Olvera, Kerstin Kiefer, Christian Brander, Peter Steinberger, Rubén Vicente
The Journal of Immunology December 14, 2018, ji1800689; DOI: 10.4049/jimmunol.1800689

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Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery
Natalia Colomar-Carando, Alberto Meseguer, Iván Company-Garrido, Sabrina Jutz, Víctor Herrera-Fernández, Alex Olvera, Kerstin Kiefer, Christian Brander, Peter Steinberger, Rubén Vicente
The Journal of Immunology December 14, 2018, ji1800689; DOI: 10.4049/jimmunol.1800689
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Print ISSN 0022-1767        Online ISSN 1550-6606