Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.

<h4>Background</h4>A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack,...

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Autores principales:	Petter Brodin, Tadepally Lakshmikanth, Ramit Mehr, Maria H Johansson, Adil Doganay Duru, Adnane Achour, Mali Salmon-Divon, Klas Kärre, Petter Höglund, Sofia Johansson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6242f9fce31942b8b6b1ccec4cbaf9fa
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spelling	oai:doaj.org-article:6242f9fce31942b8b6b1ccec4cbaf9fa2021-11-18T07:03:41ZNatural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.1932-620310.1371/journal.pone.0013174https://doaj.org/article/6242f9fce31942b8b6b1ccec4cbaf9fa2010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20957233/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known.<h4>Methodology/principal findings</h4>In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further effect on the degree of Ly49 downmodulation. Furthermore, a single MHC class I allele could downmodulate up to three Ly49 receptors on individual NK cells. Only when NK cells simultaneously expressed several Ly49 receptors and hemizygous MHC class I levels, a putative threshold for Ly49 downmodulation was reached.<h4>Conclusion</h4>Collectively, our findings suggest that in interactions between NK cells and normal untransformed cells, MHC class I molecules are in most cases expressed in excess compared to what is functionally needed to ensure self tolerance and to induce maximal Ly49 downmodulation. We speculate that the reason for this is to maintain a safety margin for otherwise normal, autologous cells over a range of MHC class I expression levels, in order to ensure robustness in NK cell tolerance.Petter BrodinTadepally LakshmikanthRamit MehrMaria H JohanssonAdil Doganay DuruAdnane AchourMali Salmon-DivonKlas KärrePetter HöglundSofia JohanssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Petter Brodin Tadepally Lakshmikanth Ramit Mehr Maria H Johansson Adil Doganay Duru Adnane Achour Mali Salmon-Divon Klas Kärre Petter Höglund Sofia Johansson Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
description	<h4>Background</h4>A major group of murine inhibitory receptors on Natural Killer (NK) cells belong to the Ly49 receptor family and recognize MHC class I molecules. Infected or transformed target cells frequently downmodulate MHC class I molecules and can thus avoid CD8(+) T cell attack, but may at the same time develop NK cell sensitivity, due to failure to express inhibitory ligands for Ly49 receptors. The extent of MHC class I downregulation needed on normal cells to trigger NK cell effector functions is not known.<h4>Methodology/principal findings</h4>In this study, we show that cells expressing MHC class I to levels well below half of the host level are tolerated in an in vivo assay in mice. Hemizygous expression (expression from only one allele) of MHC class I was sufficient to induce Ly49 receptor downmodulation on NK cells to a similar degree as homozygous expression, despite a strongly reduced cell surface level of MHC class I. Co-expression of weaker MHC class I ligands in the host did not have any further effect on the degree of Ly49 downmodulation. Furthermore, a single MHC class I allele could downmodulate up to three Ly49 receptors on individual NK cells. Only when NK cells simultaneously expressed several Ly49 receptors and hemizygous MHC class I levels, a putative threshold for Ly49 downmodulation was reached.<h4>Conclusion</h4>Collectively, our findings suggest that in interactions between NK cells and normal untransformed cells, MHC class I molecules are in most cases expressed in excess compared to what is functionally needed to ensure self tolerance and to induce maximal Ly49 downmodulation. We speculate that the reason for this is to maintain a safety margin for otherwise normal, autologous cells over a range of MHC class I expression levels, in order to ensure robustness in NK cell tolerance.
format	article
author	Petter Brodin Tadepally Lakshmikanth Ramit Mehr Maria H Johansson Adil Doganay Duru Adnane Achour Mali Salmon-Divon Klas Kärre Petter Höglund Sofia Johansson
author_facet	Petter Brodin Tadepally Lakshmikanth Ramit Mehr Maria H Johansson Adil Doganay Duru Adnane Achour Mali Salmon-Divon Klas Kärre Petter Höglund Sofia Johansson
author_sort	Petter Brodin
title	Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
title_short	Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
title_full	Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
title_fullStr	Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
title_full_unstemmed	Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.
title_sort	natural killer cell tolerance persists despite significant reduction of self mhc class i on normal target cells in mice.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/6242f9fce31942b8b6b1ccec4cbaf9fa
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Natural killer cell tolerance persists despite significant reduction of self MHC class I on normal target cells in mice.

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