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Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors
BACKGROUND AND OBJECTIVES: We posit the involvement of the natural killer group 2D (NKG2D) pathway in multiple sclerosis (MS) pathology via the presence of specific NKG2D ligands (NKG2DLs). We aim to evaluate the expression of NKG2DLs in the CNS and CSF of patients with MS and to identify cellular s...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656234/ https://www.ncbi.nlm.nih.gov/pubmed/34873031 http://dx.doi.org/10.1212/NXI.0000000000001119 |
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author | Carmena Moratalla, Ana Carpentier Solorio, Yves Lemaitre, Florent Farzam-kia, Negar Levert, Annie Zandee, Stephanie E.J. Lahav, Boaz Guimond, Jean Victor Haddad, Elie Girard, Marc Duquette, Pierre Larochelle, Catherine Prat, Alexandre Arbour, Nathalie |
author_facet | Carmena Moratalla, Ana Carpentier Solorio, Yves Lemaitre, Florent Farzam-kia, Negar Levert, Annie Zandee, Stephanie E.J. Lahav, Boaz Guimond, Jean Victor Haddad, Elie Girard, Marc Duquette, Pierre Larochelle, Catherine Prat, Alexandre Arbour, Nathalie |
author_sort | Carmena Moratalla, Ana |
collection | PubMed |
description | BACKGROUND AND OBJECTIVES: We posit the involvement of the natural killer group 2D (NKG2D) pathway in multiple sclerosis (MS) pathology via the presence of specific NKG2D ligands (NKG2DLs). We aim to evaluate the expression of NKG2DLs in the CNS and CSF of patients with MS and to identify cellular stressors inducing the expression of UL16-binding protein 4 (ULBP4), the only detectable NKG2DL. Finally, we evaluate the impact of ULBP4 on functions such as cytokine production and motility by CD8(+) T lymphocytes, a subset largely expressing NKG2D, the cognate receptor. METHODS: Human postmortem brain samples and CSF from patients with MS and controls were used to evaluate NKG2DL expression. In vitro assays using primary cultures of human astrocytes and neurons were performed to identify stressors inducing ULBP4 expression. Human CD8(+) T lymphocytes from MS donors and age/sex-matched healthy controls were isolated to evaluate the functional impact of soluble ULBP4. RESULTS: We detected mRNA coding for the 8 identified human NKG2DLs in brain samples from patients with MS and controls, but only ULBP4 protein expression was detectable by Western blot. ULBP4 levels were greater in patients with MS, particularly in active and chronic active lesions and normal-appearing white matter, compared with normal-appearing gray matter from MS donors and white and gray matter from controls. Soluble ULBP4 was also detected in CSF of patients with MS and controls, but a smaller shed/soluble form of 25 kDa was significantly elevated in CSF from female patients with MS compared with controls and male patients with MS. Our data indicate that soluble ULBP4 affects various functions of CD8(+) T lymphocytes. First, it enhanced the production of the proinflammatory cytokines GM-CSF and interferon-γ (IFNγ). Second, it increased CD8(+) T lymphocyte motility and favored a kinapse-like behavior when cultured in the presence of human astrocytes. CD8(+) T lymphocytes from patients with MS were especially altered by the presence of soluble ULBP4 compared with healthy controls. DISCUSSION: Our study provides new evidence for the involvement of NKG2D and its ligand ULBP4 in MS pathology. Our results point to ULBP4 as a viable target to specifically block 1 component of the NKG2D pathway without altering immune surveillance involving other NKG2DL. |
format | Online Article Text |
id | pubmed-8656234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-86562342021-12-09 Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors Carmena Moratalla, Ana Carpentier Solorio, Yves Lemaitre, Florent Farzam-kia, Negar Levert, Annie Zandee, Stephanie E.J. Lahav, Boaz Guimond, Jean Victor Haddad, Elie Girard, Marc Duquette, Pierre Larochelle, Catherine Prat, Alexandre Arbour, Nathalie Neurol Neuroimmunol Neuroinflamm Article BACKGROUND AND OBJECTIVES: We posit the involvement of the natural killer group 2D (NKG2D) pathway in multiple sclerosis (MS) pathology via the presence of specific NKG2D ligands (NKG2DLs). We aim to evaluate the expression of NKG2DLs in the CNS and CSF of patients with MS and to identify cellular stressors inducing the expression of UL16-binding protein 4 (ULBP4), the only detectable NKG2DL. Finally, we evaluate the impact of ULBP4 on functions such as cytokine production and motility by CD8(+) T lymphocytes, a subset largely expressing NKG2D, the cognate receptor. METHODS: Human postmortem brain samples and CSF from patients with MS and controls were used to evaluate NKG2DL expression. In vitro assays using primary cultures of human astrocytes and neurons were performed to identify stressors inducing ULBP4 expression. Human CD8(+) T lymphocytes from MS donors and age/sex-matched healthy controls were isolated to evaluate the functional impact of soluble ULBP4. RESULTS: We detected mRNA coding for the 8 identified human NKG2DLs in brain samples from patients with MS and controls, but only ULBP4 protein expression was detectable by Western blot. ULBP4 levels were greater in patients with MS, particularly in active and chronic active lesions and normal-appearing white matter, compared with normal-appearing gray matter from MS donors and white and gray matter from controls. Soluble ULBP4 was also detected in CSF of patients with MS and controls, but a smaller shed/soluble form of 25 kDa was significantly elevated in CSF from female patients with MS compared with controls and male patients with MS. Our data indicate that soluble ULBP4 affects various functions of CD8(+) T lymphocytes. First, it enhanced the production of the proinflammatory cytokines GM-CSF and interferon-γ (IFNγ). Second, it increased CD8(+) T lymphocyte motility and favored a kinapse-like behavior when cultured in the presence of human astrocytes. CD8(+) T lymphocytes from patients with MS were especially altered by the presence of soluble ULBP4 compared with healthy controls. DISCUSSION: Our study provides new evidence for the involvement of NKG2D and its ligand ULBP4 in MS pathology. Our results point to ULBP4 as a viable target to specifically block 1 component of the NKG2D pathway without altering immune surveillance involving other NKG2DL. Lippincott Williams & Wilkins 2021-12-06 /pmc/articles/PMC8656234/ /pubmed/34873031 http://dx.doi.org/10.1212/NXI.0000000000001119 Text en Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Article Carmena Moratalla, Ana Carpentier Solorio, Yves Lemaitre, Florent Farzam-kia, Negar Levert, Annie Zandee, Stephanie E.J. Lahav, Boaz Guimond, Jean Victor Haddad, Elie Girard, Marc Duquette, Pierre Larochelle, Catherine Prat, Alexandre Arbour, Nathalie Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors |
title | Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors |
title_full | Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors |
title_fullStr | Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors |
title_full_unstemmed | Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors |
title_short | Stress Signal ULBP4, an NKG2D Ligand, Is Upregulated in Multiple Sclerosis and Shapes CD8(+) T-Cell Behaviors |
title_sort | stress signal ulbp4, an nkg2d ligand, is upregulated in multiple sclerosis and shapes cd8(+) t-cell behaviors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656234/ https://www.ncbi.nlm.nih.gov/pubmed/34873031 http://dx.doi.org/10.1212/NXI.0000000000001119 |
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