Dataset Information

Osteopontin associates with brain T_RM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.

ABSTRACT: The human brain is populated by perivascular T cells with a tissue-resident memory T (T_RM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8⁺ and CD4⁺ CD69⁺ T cells revealed T_RM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter T cells in MS brains. Genes up-regulated in brain T_RM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T cell activity. In line with their parenchymal localization and the increased presence of OPN in active MS lesions, we noticed a reduced production of inflammatory cytokines IL-2, TNF, and IFNγ by lesion-derived CD8⁺ and CD4⁺ T cells ex vivo. Our study reports traits of brain T_RM cells and reveals their tight control in MS lesions.

SUBMITTER: Hsiao CC

PROVIDER: S-EPMC9804143 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Osteopontin associates with brain TRM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.

Hsiao Cheng-Chih CC Engelenburg Hendrik J HJ Jongejan Aldo A Zhu Jing J Zhang Baohong B Mingueneau Michael M Moerland Perry D PD Huitinga Inge I Smolders Joost J Hamann Jörg J

iScience 20221209 1

The human brain is populated by perivascular T cells with a tissue-resident memory T (TRM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8+ and CD4+ CD69+ T cells revealed TRM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matte ...[more]

PMID: 36594029

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Project description:ObjectiveFinding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells.Materials and methodsBased on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database.ResultsWe obtained 50 hub target genes for CD4+ T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19+ B cells and 15 target pathways for CD4+ T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways.ConclusionWe found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.

Dataset Information

Osteopontin associates with brain T_RM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.

Publications

Osteopontin associates with brain T<sub>RM</sub>-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.

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