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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197390/?tool=EBI |
| _version_ | 1818839398158958592 |
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| 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 |
| collection | DOAJ |
| 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. |
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| format | Article |
| id | doaj.art-4d4aa06cbc694aa491852a44bf65b1d0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T03:53:39Z |
| publishDate | 2009-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-4d4aa06cbc694aa491852a44bf65b1d02022-12-21T20:36:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0142e440510.1371/journal.pone.0004405PD-1 regulates neural damage in oligodendroglia-induced inflammation.Antje KronerNicholas SchwabChi Wang IpChristoph LederKlaus-Armin NaveMathias MäurerHeinz WiendlRudolf MartiniWe 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197390/?tool=EBI |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | PD-1 regulates neural damage in oligodendroglia-induced inflammation. |
| title_sort | pd 1 regulates neural damage in oligodendroglia induced inflammation |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19197390/?tool=EBI |
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