Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells

Natural killer (NK) cells play a critical role in controlling murine cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein b...

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Autores principales: Parikh, Bijal A., Piersma, Sytse J., Pak-Wittel, Melissa A., Yang, Liping, Schreiber, Robert D., Yokoyama, Wayne M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697817/
https://www.ncbi.nlm.nih.gov/pubmed/26720279
http://dx.doi.org/10.1371/journal.ppat.1005323
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author Parikh, Bijal A.
Piersma, Sytse J.
Pak-Wittel, Melissa A.
Yang, Liping
Schreiber, Robert D.
Yokoyama, Wayne M.
author_facet Parikh, Bijal A.
Piersma, Sytse J.
Pak-Wittel, Melissa A.
Yang, Liping
Schreiber, Robert D.
Yokoyama, Wayne M.
author_sort Parikh, Bijal A.
collection PubMed
description Natural killer (NK) cells play a critical role in controlling murine cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein by Ly49H is sufficient for effective control of MCMV infection. Additionally, during the host response to infection, distinct immune and non-immune cells elaborate a variety of pleiotropic cytokines which have the potential to impact viral pathogenesis, NK cells, and other immune functions, both directly and indirectly. While the effects of various immune deficiencies have been examined for general antiviral phenotypes, their direct effects on Ly49H-dependent MCMV control are poorly understood. To specifically interrogate Ly49H-dependent functions, herein we employed an in vivo viral competition approach to show Ly49H-dependent MCMV control is specifically mediated through cytotoxicity but not IFNγ production. Whereas m157 induced Ly49H-dependent degranulation, efficient cytotoxicity also required either IL-12 or type I interferon (IFN-I) which acted directly on NK cells to produce granzyme B. These studies demonstrate that both of these distinct NK cell-intrinsic mechanisms are integrated for optimal viral control by NK cells.
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spelling pubmed-46978172016-01-13 Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells Parikh, Bijal A. Piersma, Sytse J. Pak-Wittel, Melissa A. Yang, Liping Schreiber, Robert D. Yokoyama, Wayne M. PLoS Pathog Research Article Natural killer (NK) cells play a critical role in controlling murine cytomegalovirus (MCMV) and can mediate both cytokine production and direct cytotoxicity. The NK cell activation receptor, Ly49H, is responsible for genetic resistance to MCMV in C57BL/6 mice. Recognition of the viral m157 protein by Ly49H is sufficient for effective control of MCMV infection. Additionally, during the host response to infection, distinct immune and non-immune cells elaborate a variety of pleiotropic cytokines which have the potential to impact viral pathogenesis, NK cells, and other immune functions, both directly and indirectly. While the effects of various immune deficiencies have been examined for general antiviral phenotypes, their direct effects on Ly49H-dependent MCMV control are poorly understood. To specifically interrogate Ly49H-dependent functions, herein we employed an in vivo viral competition approach to show Ly49H-dependent MCMV control is specifically mediated through cytotoxicity but not IFNγ production. Whereas m157 induced Ly49H-dependent degranulation, efficient cytotoxicity also required either IL-12 or type I interferon (IFN-I) which acted directly on NK cells to produce granzyme B. These studies demonstrate that both of these distinct NK cell-intrinsic mechanisms are integrated for optimal viral control by NK cells. Public Library of Science 2015-12-31 /pmc/articles/PMC4697817/ /pubmed/26720279 http://dx.doi.org/10.1371/journal.ppat.1005323 Text en © 2015 Parikh et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Parikh, Bijal A.
Piersma, Sytse J.
Pak-Wittel, Melissa A.
Yang, Liping
Schreiber, Robert D.
Yokoyama, Wayne M.
Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells
title Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells
title_full Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells
title_fullStr Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells
title_full_unstemmed Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells
title_short Dual Requirement of Cytokine and Activation Receptor Triggering for Cytotoxic Control of Murine Cytomegalovirus by NK Cells
title_sort dual requirement of cytokine and activation receptor triggering for cytotoxic control of murine cytomegalovirus by nk cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697817/
https://www.ncbi.nlm.nih.gov/pubmed/26720279
http://dx.doi.org/10.1371/journal.ppat.1005323
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