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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter (Circulation)

ABSTRACT: Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter (Circulation)

PROVIDER: PRJNA891736 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21957100_1.fastq.gz	Fastqsanger.gz
	SRR21957100_2.fastq.gz	Fastqsanger.gz
	SRR21957101_1.fastq.gz	Fastqsanger.gz
	SRR21957101_2.fastq.gz	Fastqsanger.gz
	SRR21957102_1.fastq.gz	Fastqsanger.gz

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter (Circulation)

Project description:The human brain is populated by perivascular CD8+ and CD4+ T cells with a tissue-resident memory T (TRM)-cell phenotype. In multiple sclerosis (MS), these cells associate with white matter (WM) and, to a lesser extent, grey matter (GM) lesions. We here investigated the transcriptional and functional profile of brain-resident T cells. Of n=11 subsequent post-mortem brain donors, we isolated CD8+ and CD4+ effector memory and effector memory re-expressing CD45RA T cells from blood and CD8+ and CD4+ CD69+ T cells from corpus callosum WM and cortical GM. Additionally, brain CD69+ T cells were sorted from subcortical WM, corpus callosum WM, and medulla WM/GM of n=3–5 brain donors as well as from paired normal-appearing WM and GM and from WM and GM lesions of n=6 MS brain donors. In all donors, WM and GM T cells were overwhelmingly CD69+CD103+/-. Bulk RNA sequencing of CD8+ and CD4+ CD69+ T cells revealed TRM-cell signatures, as marked by differential expression of, among others, SELL (CD62L), ITGA1 (CD49a), and S1PR1. Notably, gene expression hardly differed between lesional and normal-appearing WM CD8+ and CD4+ CD69+ T cells in MS brains. Genes up-regulated in brain TRM 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 the increased presence of OPN in active MS lesions, we noticed a reduced production of the inflammatory cytokines IL-2, TNF, and IFNγ by MS lesion-derived CD8+ and CD4+ T cells ex vivo. This study discloses essential characteristics of human brain CD8+ and CD4+ TRM cells in non-MS and MS post-mortem WM and GM, reports OPN as a generic product of brain-resident immune cells, and shows a tight control of the activation state of TRM cells in MS lesions.

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (MS)

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (Location)

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis

Project description:Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (Location)

Project description:Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (Location)

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Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (MS)

Project description:Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (MS)

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Multiple sclerosis cortical normal-appearing grey matter and control grey matter

Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain. Among characteristics of MS pathology are cortical grey matter abnormalities, which have been linked to clinical signs such as cognitive impairment. To understand MS cortical grey matter pathogenesis, we performed differential gene expression analysis of MS normal appearing grey matter (NAGM) and control grey matter. HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of grey matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. Our data indicate that increased HLA-DRB1 expression in the brain of MS patients may be an important factor in how the HLA-DR15 haplotype contributes to MS risk in the target organ.

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