PD-1 regulates neural damage in oligodendroglia-induced inflammation.

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-re...

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Autores principales:	Antje Kroner, Nicholas Schwab, Chi Wang Ip, Christoph Leder, Klaus-Armin Nave, Mathias Mäurer, Heinz Wiendl, Rudolf Martini
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4d4aa06cbc694aa491852a44bf65b1d0
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spelling	oai:doaj.org-article:4d4aa06cbc694aa491852a44bf65b1d02021-11-25T06:17:26ZPD-1 regulates neural damage in oligodendroglia-induced inflammation.1932-620310.1371/journal.pone.0004405https://doaj.org/article/4d4aa06cbc694aa491852a44bf65b1d02009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197390/?tool=EBIhttps://doaj.org/toc/1932-6203We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.Antje KronerNicholas SchwabChi Wang IpChristoph LederKlaus-Armin NaveMathias MäurerHeinz WiendlRudolf MartiniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 2, p e4405 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antje Kroner Nicholas Schwab Chi Wang Ip Christoph Leder Klaus-Armin Nave Mathias Mäurer Heinz Wiendl Rudolf Martini PD-1 regulates neural damage in oligodendroglia-induced inflammation.
description	We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.
format	article
author	Antje Kroner Nicholas Schwab Chi Wang Ip Christoph Leder Klaus-Armin Nave Mathias Mäurer Heinz Wiendl Rudolf Martini
author_facet	Antje Kroner Nicholas Schwab Chi Wang Ip Christoph Leder Klaus-Armin Nave Mathias Mäurer Heinz Wiendl Rudolf Martini
author_sort	Antje Kroner
title	PD-1 regulates neural damage in oligodendroglia-induced inflammation.
title_short	PD-1 regulates neural damage in oligodendroglia-induced inflammation.
title_full	PD-1 regulates neural damage in oligodendroglia-induced inflammation.
title_fullStr	PD-1 regulates neural damage in oligodendroglia-induced inflammation.
title_full_unstemmed	PD-1 regulates neural damage in oligodendroglia-induced inflammation.
title_sort	pd-1 regulates neural damage in oligodendroglia-induced inflammation.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/4d4aa06cbc694aa491852a44bf65b1d0
work_keys_str_mv	AT antjekroner pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT nicholasschwab pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT chiwangip pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT christophleder pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT klausarminnave pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT mathiasmaurer pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT heinzwiendl pd1regulatesneuraldamageinoligodendrogliainducedinflammation AT rudolfmartini pd1regulatesneuraldamageinoligodendrogliainducedinflammation
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PD-1 regulates neural damage in oligodendroglia-induced inflammation.

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