Single-cell transcriptomics reveals the interaction between peripheral CD4+ CTLs and mesencephalic endothelial cells mediated by IFNG in Parkinson's disease
Parkinson's disease (PD) is characterized by dopaminergic neurons degeneration in the substantia nigra pars compacta. Increasing evidence indicates that peripheral CD4+ T cells, a vital pathological component of PD, have been implicated in systemic inflammation activation, blood-brain barrier (...
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| Veröffentlicht in: | Computers in biology and medicine 2023-05, Vol.158, p.106801-106801, Article 106801 |
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| creator | Yan, Shi Si, Yao Zhou, Wenyang Cheng, Rui Wang, Pingping Wang, Di Ding, Wencai Shi, Wanying Jiang, Qinghua Yang, Fan Yao, Lifen |
| description | Parkinson's disease (PD) is characterized by dopaminergic neurons degeneration in the substantia nigra pars compacta. Increasing evidence indicates that peripheral CD4+ T cells, a vital pathological component of PD, have been implicated in systemic inflammation activation, blood-brain barrier (BBB) dysfunction, central nervous system infiltration, and consequent neurons degeneration. However, there is no consensus on CD4+ T cell types' exact phenotypic characteristics in systemic inflammation and the mechanism of CD4+ T cells traffic into the BBB in patients with PD. In this study, we employed single-cell RNA sequencing (scRNA-seq) to elucidate the potential mechanism of T cells on the breakdown of BBB. The PD-associated Cytotoxic CD4+ T cells (CD4+ CTLs) were characterized by a significant increase in proportion as well as enhancement of interferon-gamma (IFNG) response and cell adhesion. Meanwhile, TBX21, IRF1 and NFATC2, identified as the key transcription factors in effector CD4+ T cells differentiation, induced overexpression of target genes-IFNG in CD4+ CTLs. Interestingly, endothelial cells (ECs) in PD patients were discovered to be more responsive to IFNG than other cell types of midbrain. Furthermore, the cell-cell communication analysis between CD4+ T cells and midbrain cells identified IFNG/IFNGR1 and SPP1/ITGB1 as the ligand-receptor pairs to mediate CD4+ CTLs' infiltration into the central nervous system (CNS) through the weakened ECs' tight junction. Together, these results suggested that PD-specific peripheral CD4+ CTLs might influence BBB function by migrating to mesencephalic endothelial cells (ECs) and activating the IFNG response in ECs.
•Within the PBMCs, CD4+ CTLs are most abundant in patients with PD.•Peripheral CD4+ CTLs are characterized by IFNG response and cell adhesion.•TBX21, IRF1 and NFATC2 are the key TFs participating in CD4+ CTLs differentiation and inducing IFNG production.•Mesencephalic ECs in PD undergo IFNG response.•Interaction between CD4+ CTLs and ECs reveals CD4+ CTLs’ upregulated migration and ECs’ activated IFNG response. |
| doi_str_mv | 10.1016/j.compbiomed.2023.106801 |
| format | Article |
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•Within the PBMCs, CD4+ CTLs are most abundant in patients with PD.•Peripheral CD4+ CTLs are characterized by IFNG response and cell adhesion.•TBX21, IRF1 and NFATC2 are the key TFs participating in CD4+ CTLs differentiation and inducing IFNG production.•Mesencephalic ECs in PD undergo IFNG response.•Interaction between CD4+ CTLs and ECs reveals CD4+ CTLs’ upregulated migration and ECs’ activated IFNG response.</description><identifier>ISSN: 0010-4825</identifier><identifier>EISSN: 1879-0534</identifier><identifier>DOI: 10.1016/j.compbiomed.2023.106801</identifier><identifier>PMID: 36989741</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Alzheimer's disease ; Blood-brain barrier ; CD4 antigen ; CD4+ CTLs ; CD4-Positive T-Lymphocytes - metabolism ; CD4-Positive T-Lymphocytes - pathology ; Cell adhesion ; Cell differentiation ; Cell interactions ; Cells ; Central nervous system ; Cytotoxicity ; Degeneration ; Dopamine receptors ; Effector cells ; Endothelial cells ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Gene expression ; Gene sequencing ; Genomics ; Humans ; IFNG response ; Infiltration ; Inflammation ; Interferon regulatory factor 1 ; Interferon-gamma - metabolism ; Ligands ; Lymphocytes ; Lymphocytes T ; Mesencephalon ; Mesencephalon - metabolism ; Mesencephalon - pathology ; Movement disorders ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Parkinson Disease - metabolism ; Parkinson's disease ; Patients ; scRNA-seq ; Substantia nigra ; Transcription factors ; Transcriptome - genetics ; Transcriptomics ; γ-Interferon</subject><ispartof>Computers in biology and medicine, 2023-05, Vol.158, p.106801-106801, Article 106801</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><rights>2023. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c317t-5e223d93ee315fe029014d567027d41afcfd5d956e4ec8171709847e55af7a2f3</citedby><cites>FETCH-LOGICAL-c317t-5e223d93ee315fe029014d567027d41afcfd5d956e4ec8171709847e55af7a2f3</cites><orcidid>0000-0002-8809-6523</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0010482523002664$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36989741$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, Shi</creatorcontrib><creatorcontrib>Si, Yao</creatorcontrib><creatorcontrib>Zhou, Wenyang</creatorcontrib><creatorcontrib>Cheng, Rui</creatorcontrib><creatorcontrib>Wang, Pingping</creatorcontrib><creatorcontrib>Wang, Di</creatorcontrib><creatorcontrib>Ding, Wencai</creatorcontrib><creatorcontrib>Shi, Wanying</creatorcontrib><creatorcontrib>Jiang, Qinghua</creatorcontrib><creatorcontrib>Yang, Fan</creatorcontrib><creatorcontrib>Yao, Lifen</creatorcontrib><title>Single-cell transcriptomics reveals the interaction between peripheral CD4+ CTLs and mesencephalic endothelial cells mediated by IFNG in Parkinson's disease</title><title>Computers in biology and medicine</title><addtitle>Comput Biol Med</addtitle><description>Parkinson's disease (PD) is characterized by dopaminergic neurons degeneration in the substantia nigra pars compacta. Increasing evidence indicates that peripheral CD4+ T cells, a vital pathological component of PD, have been implicated in systemic inflammation activation, blood-brain barrier (BBB) dysfunction, central nervous system infiltration, and consequent neurons degeneration. However, there is no consensus on CD4+ T cell types' exact phenotypic characteristics in systemic inflammation and the mechanism of CD4+ T cells traffic into the BBB in patients with PD. In this study, we employed single-cell RNA sequencing (scRNA-seq) to elucidate the potential mechanism of T cells on the breakdown of BBB. The PD-associated Cytotoxic CD4+ T cells (CD4+ CTLs) were characterized by a significant increase in proportion as well as enhancement of interferon-gamma (IFNG) response and cell adhesion. Meanwhile, TBX21, IRF1 and NFATC2, identified as the key transcription factors in effector CD4+ T cells differentiation, induced overexpression of target genes-IFNG in CD4+ CTLs. Interestingly, endothelial cells (ECs) in PD patients were discovered to be more responsive to IFNG than other cell types of midbrain. Furthermore, the cell-cell communication analysis between CD4+ T cells and midbrain cells identified IFNG/IFNGR1 and SPP1/ITGB1 as the ligand-receptor pairs to mediate CD4+ CTLs' infiltration into the central nervous system (CNS) through the weakened ECs' tight junction. Together, these results suggested that PD-specific peripheral CD4+ CTLs might influence BBB function by migrating to mesencephalic endothelial cells (ECs) and activating the IFNG response in ECs.
•Within the PBMCs, CD4+ CTLs are most abundant in patients with PD.•Peripheral CD4+ CTLs are characterized by IFNG response and cell adhesion.•TBX21, IRF1 and NFATC2 are the key TFs participating in CD4+ CTLs differentiation and inducing IFNG production.•Mesencephalic ECs in PD undergo IFNG response.•Interaction between CD4+ CTLs and ECs reveals CD4+ CTLs’ upregulated migration and ECs’ activated IFNG response.</description><subject>Alzheimer's disease</subject><subject>Blood-brain barrier</subject><subject>CD4 antigen</subject><subject>CD4+ CTLs</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>CD4-Positive T-Lymphocytes - pathology</subject><subject>Cell adhesion</subject><subject>Cell differentiation</subject><subject>Cell interactions</subject><subject>Cells</subject><subject>Central nervous system</subject><subject>Cytotoxicity</subject><subject>Degeneration</subject><subject>Dopamine receptors</subject><subject>Effector cells</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Genomics</subject><subject>Humans</subject><subject>IFNG response</subject><subject>Infiltration</subject><subject>Inflammation</subject><subject>Interferon regulatory factor 1</subject><subject>Interferon-gamma - metabolism</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Mesencephalon</subject><subject>Mesencephalon - metabolism</subject><subject>Mesencephalon - pathology</subject><subject>Movement disorders</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurons</subject><subject>Parkinson Disease - metabolism</subject><subject>Parkinson's disease</subject><subject>Patients</subject><subject>scRNA-seq</subject><subject>Substantia nigra</subject><subject>Transcription factors</subject><subject>Transcriptome - genetics</subject><subject>Transcriptomics</subject><subject>γ-Interferon</subject><issn>0010-4825</issn><issn>1879-0534</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkcGKFDEQhoMo7rj6ChLwoCA9VpLuTvdRR3ddGFRwPYdMUu1k7E7aJLOy7-LDmmZ2Ebx4Kqj66v-L-gmhDNYMWPvmsDZhmncuTGjXHLgo7bYD9oCsWCf7ChpRPyQrAAZV3fHmjDxJ6QAANQh4TM5E23e9rNmK_P7q_PcRK4PjSHPUPpno5hwmZxKNeIN6TDTvkTqfMWqTXfB0h_kXoqczFnZf2iPdvK9f0831NlHtLZ0woTc47_XoDEVvQ5EYXeEWn1Tm1umMlu5u6dXFp8uiTr_o-MP5FPzLRK1LqBM-JY-G4o_P7uo5-Xbx4Xrzsdp-vrzavN1WRjCZqwY5F7YXiII1AwLvgdW2aSVwaWumBzPYxvZNizWajkkmoe9qiU2jB6n5IM7Jq5PuHMPPI6asJpeWS7XHcEyKy75oCpBtQV_8gx7CMfpyneIlgL4trgvVnSgTQ0oRBzVHN-l4qxioJUF1UH8TVEuC6pRgWX1-Z3DcLbP7xfvICvDuBGD5yI3DqJJxy7eti2iyssH93-UPg_Wy5A</recordid><startdate>202305</startdate><enddate>202305</enddate><creator>Yan, Shi</creator><creator>Si, Yao</creator><creator>Zhou, Wenyang</creator><creator>Cheng, Rui</creator><creator>Wang, Pingping</creator><creator>Wang, Di</creator><creator>Ding, Wencai</creator><creator>Shi, Wanying</creator><creator>Jiang, Qinghua</creator><creator>Yang, Fan</creator><creator>Yao, Lifen</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AL</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>JQ2</scope><scope>K7-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0N</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>M7Z</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8809-6523</orcidid></search><sort><creationdate>202305</creationdate><title>Single-cell transcriptomics reveals the interaction between peripheral CD4+ CTLs and mesencephalic endothelial cells mediated by IFNG in Parkinson's disease</title><author>Yan, Shi ; Si, Yao ; Zhou, Wenyang ; Cheng, Rui ; Wang, Pingping ; Wang, Di ; Ding, Wencai ; Shi, Wanying ; Jiang, Qinghua ; Yang, Fan ; Yao, Lifen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c317t-5e223d93ee315fe029014d567027d41afcfd5d956e4ec8171709847e55af7a2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alzheimer's disease</topic><topic>Blood-brain barrier</topic><topic>CD4 antigen</topic><topic>CD4+ CTLs</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>CD4-Positive T-Lymphocytes - pathology</topic><topic>Cell adhesion</topic><topic>Cell differentiation</topic><topic>Cell interactions</topic><topic>Cells</topic><topic>Central nervous system</topic><topic>Cytotoxicity</topic><topic>Degeneration</topic><topic>Dopamine receptors</topic><topic>Effector cells</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelial Cells - pathology</topic><topic>Gene expression</topic><topic>Gene sequencing</topic><topic>Genomics</topic><topic>Humans</topic><topic>IFNG response</topic><topic>Infiltration</topic><topic>Inflammation</topic><topic>Interferon regulatory factor 1</topic><topic>Interferon-gamma - metabolism</topic><topic>Ligands</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Mesencephalon</topic><topic>Mesencephalon - metabolism</topic><topic>Mesencephalon - pathology</topic><topic>Movement disorders</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neurons</topic><topic>Parkinson Disease - 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Academic</collection><jtitle>Computers in biology and medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yan, Shi</au><au>Si, Yao</au><au>Zhou, Wenyang</au><au>Cheng, Rui</au><au>Wang, Pingping</au><au>Wang, Di</au><au>Ding, Wencai</au><au>Shi, Wanying</au><au>Jiang, Qinghua</au><au>Yang, Fan</au><au>Yao, Lifen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-cell transcriptomics reveals the interaction between peripheral CD4+ CTLs and mesencephalic endothelial cells mediated by IFNG in Parkinson's disease</atitle><jtitle>Computers in biology and medicine</jtitle><addtitle>Comput Biol Med</addtitle><date>2023-05</date><risdate>2023</risdate><volume>158</volume><spage>106801</spage><epage>106801</epage><pages>106801-106801</pages><artnum>106801</artnum><issn>0010-4825</issn><eissn>1879-0534</eissn><abstract>Parkinson's disease (PD) is characterized by dopaminergic neurons degeneration in the substantia nigra pars compacta. Increasing evidence indicates that peripheral CD4+ T cells, a vital pathological component of PD, have been implicated in systemic inflammation activation, blood-brain barrier (BBB) dysfunction, central nervous system infiltration, and consequent neurons degeneration. However, there is no consensus on CD4+ T cell types' exact phenotypic characteristics in systemic inflammation and the mechanism of CD4+ T cells traffic into the BBB in patients with PD. In this study, we employed single-cell RNA sequencing (scRNA-seq) to elucidate the potential mechanism of T cells on the breakdown of BBB. The PD-associated Cytotoxic CD4+ T cells (CD4+ CTLs) were characterized by a significant increase in proportion as well as enhancement of interferon-gamma (IFNG) response and cell adhesion. Meanwhile, TBX21, IRF1 and NFATC2, identified as the key transcription factors in effector CD4+ T cells differentiation, induced overexpression of target genes-IFNG in CD4+ CTLs. Interestingly, endothelial cells (ECs) in PD patients were discovered to be more responsive to IFNG than other cell types of midbrain. Furthermore, the cell-cell communication analysis between CD4+ T cells and midbrain cells identified IFNG/IFNGR1 and SPP1/ITGB1 as the ligand-receptor pairs to mediate CD4+ CTLs' infiltration into the central nervous system (CNS) through the weakened ECs' tight junction. Together, these results suggested that PD-specific peripheral CD4+ CTLs might influence BBB function by migrating to mesencephalic endothelial cells (ECs) and activating the IFNG response in ECs.
•Within the PBMCs, CD4+ CTLs are most abundant in patients with PD.•Peripheral CD4+ CTLs are characterized by IFNG response and cell adhesion.•TBX21, IRF1 and NFATC2 are the key TFs participating in CD4+ CTLs differentiation and inducing IFNG production.•Mesencephalic ECs in PD undergo IFNG response.•Interaction between CD4+ CTLs and ECs reveals CD4+ CTLs’ upregulated migration and ECs’ activated IFNG response.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>36989741</pmid><doi>10.1016/j.compbiomed.2023.106801</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8809-6523</orcidid></addata></record> |
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| ispartof | Computers in biology and medicine, 2023-05, Vol.158, p.106801-106801, Article 106801 |
| issn | 0010-4825 1879-0534 |
| language | eng |
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| subjects | Alzheimer's disease Blood-brain barrier CD4 antigen CD4+ CTLs CD4-Positive T-Lymphocytes - metabolism CD4-Positive T-Lymphocytes - pathology Cell adhesion Cell differentiation Cell interactions Cells Central nervous system Cytotoxicity Degeneration Dopamine receptors Effector cells Endothelial cells Endothelial Cells - metabolism Endothelial Cells - pathology Gene expression Gene sequencing Genomics Humans IFNG response Infiltration Inflammation Interferon regulatory factor 1 Interferon-gamma - metabolism Ligands Lymphocytes Lymphocytes T Mesencephalon Mesencephalon - metabolism Mesencephalon - pathology Movement disorders Neurodegeneration Neurodegenerative diseases Neurons Parkinson Disease - metabolism Parkinson's disease Patients scRNA-seq Substantia nigra Transcription factors Transcriptome - genetics Transcriptomics γ-Interferon |
| title | Single-cell transcriptomics reveals the interaction between peripheral CD4+ CTLs and mesencephalic endothelial cells mediated by IFNG in Parkinson's disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T21%3A54%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Single-cell%20transcriptomics%20reveals%20the%20interaction%20between%20peripheral%20CD4+%20CTLs%20and%20mesencephalic%20endothelial%20cells%20mediated%20by%20IFNG%20in%20Parkinson's%20disease&rft.jtitle=Computers%20in%20biology%20and%20medicine&rft.au=Yan,%20Shi&rft.date=2023-05&rft.volume=158&rft.spage=106801&rft.epage=106801&rft.pages=106801-106801&rft.artnum=106801&rft.issn=0010-4825&rft.eissn=1879-0534&rft_id=info:doi/10.1016/j.compbiomed.2023.106801&rft_dat=%3Cproquest_cross%3E2801966706%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2801966706&rft_id=info:pmid/36989741&rft_els_id=S0010482523002664&rfr_iscdi=true |