Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.

CD8 cytotoxic T lymphocytes (CTLs) are highly effective in defending against viral infections and tumours. They are activated through the recognition of peptide-MHC-I complex by the T-cell receptor (TCR) and co-stimulation. This cognate interaction promotes the organisation of intimate cell-cell con...

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Autores: Gómez-Morón, Álvaro, Tsukalov, Ilya, Scagnetti, Camila, Pertusa, Clara, Lozano-Prieto, Marta, Martínez-Fleta, Pedro, Requena, Silvia, Martín, Pilar, Alfranca, Aranzazu, Martin-Gayo, Enrique, Martin-Cofreces, Noa B
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/25848
Acceso en línea:https://hdl.handle.net/20.500.12105/25848
Access Level:acceso abierto
Palabra clave:T cell activation
cell asymmetry
cytoskeleton
cytotoxic CD8+ T lymphocytes
immunological synapse
metabolism
mitochondria
protein translation
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spelling Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.Gómez-Morón, ÁlvaroTsukalov, IlyaScagnetti, CamilaPertusa, ClaraLozano-Prieto, MartaMartínez-Fleta, PedroRequena, SilviaMartín, PilarAlfranca, AranzazuMartin-Gayo, EnriqueMartin-Cofreces, Noa BT cell activationcell asymmetrycytoskeletoncytotoxic CD8+ T lymphocytesimmunological synapsemetabolismmitochondriaprotein translationCD8 cytotoxic T lymphocytes (CTLs) are highly effective in defending against viral infections and tumours. They are activated through the recognition of peptide-MHC-I complex by the T-cell receptor (TCR) and co-stimulation. This cognate interaction promotes the organisation of intimate cell-cell connections that involve cytoskeleton rearrangement to enable effector function and clearance of the target cell. This is key for the asymmetric transport and mobilisation of lytic granules to the cell-cell contact, promoting directed secretion of lytic mediators such as granzymes and perforin. Mitochondria play a role in regulating CTL function by controlling processes such as calcium flux, providing the necessary energy through oxidative phosphorylation, and its own protein translation on 70S ribosomes. However, the effect of acute inhibition of cytosolic translation in the rapid response after TCR has not been studied in mature CTLs. Here, we investigated the importance of cytosolic protein synthesis in human CTLs after early TCR activation and CD28 co-stimulation for the dynamic reorganisation of the cytoskeleton, mitochondria, and lytic granules through short-term chemical inhibition of 80S ribosomes by cycloheximide and 80S and 70S by puromycin. We observed that eukaryotic ribosome function is required to allow proper asymmetric reorganisation of the tubulin cytoskeleton and mitochondria and mTOR pathway activation early upon TCR activation in human primary CTLs. Cytosolic protein translation is required to increase glucose metabolism and degranulation capacity upon TCR activation and thus to regulate the full effector function of human CTLs.Frontiers MediaComunidad de Madrid (España)Fundación La CaixaCentro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)Ministerio de Ciencia e Innovación (España)Instituto de Salud Carlos IIIUnión Europea. Comisión Europea. NextGenerationEUMinisterio de Economía y Competitividad (España)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Fundación ProCNICMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)20242024-12-0320242024-01-0120242024-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfhttps://hdl.handle.net/20.500.12105/25848reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES S2022 BMD-7209-INTEGRAMUNE-CMES LCF PR 52430018ES MCIN AEI 501100011033ES PID2022–141895OB-I00 Not availableES PID2021‐127899OB‐I00 Not availableES CNS2023–144841 Not availableES RYC2018–024374-I Not availableES PI22 01759ES PI22 01759ES PMPTA22 00090-BIOCARDIOTOXES PI22 01542ES 2022‐C23.I01.P03.S0020000003 Not availableES PEJ-2021-TL BMD-21204ES CPP2021–008385 Not availableES PRE2021–097478 Not availableES CM22 00076ES MICIN AEI 501100011033open accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/258482026-06-12T12:43:37Z
dc.title.none.fl_str_mv Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
title Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
spellingShingle Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
Gómez-Morón, Álvaro
T cell activation
cell asymmetry
cytoskeleton
cytotoxic CD8+ T lymphocytes
immunological synapse
metabolism
mitochondria
protein translation
title_short Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
title_full Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
title_fullStr Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
title_full_unstemmed Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
title_sort Cytosolic protein translation regulates cell asymmetry and function in early TCR activation of human CD8 T lymphocytes.
dc.creator.none.fl_str_mv Gómez-Morón, Álvaro
Tsukalov, Ilya
Scagnetti, Camila
Pertusa, Clara
Lozano-Prieto, Marta
Martínez-Fleta, Pedro
Requena, Silvia
Martín, Pilar
Alfranca, Aranzazu
Martin-Gayo, Enrique
Martin-Cofreces, Noa B
author Gómez-Morón, Álvaro
author_facet Gómez-Morón, Álvaro
Tsukalov, Ilya
Scagnetti, Camila
Pertusa, Clara
Lozano-Prieto, Marta
Martínez-Fleta, Pedro
Requena, Silvia
Martín, Pilar
Alfranca, Aranzazu
Martin-Gayo, Enrique
Martin-Cofreces, Noa B
author_role author
author2 Tsukalov, Ilya
Scagnetti, Camila
Pertusa, Clara
Lozano-Prieto, Marta
Martínez-Fleta, Pedro
Requena, Silvia
Martín, Pilar
Alfranca, Aranzazu
Martin-Gayo, Enrique
Martin-Cofreces, Noa B
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Comunidad de Madrid (España)
Fundación La Caixa
Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Ministerio de Ciencia e Innovación (España)
Instituto de Salud Carlos III
Unión Europea. Comisión Europea. NextGenerationEU
Ministerio de Economía y Competitividad (España)
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Fundación ProCNIC
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
dc.subject.none.fl_str_mv T cell activation
cell asymmetry
cytoskeleton
cytotoxic CD8+ T lymphocytes
immunological synapse
metabolism
mitochondria
protein translation
topic T cell activation
cell asymmetry
cytoskeleton
cytotoxic CD8+ T lymphocytes
immunological synapse
metabolism
mitochondria
protein translation
description CD8 cytotoxic T lymphocytes (CTLs) are highly effective in defending against viral infections and tumours. They are activated through the recognition of peptide-MHC-I complex by the T-cell receptor (TCR) and co-stimulation. This cognate interaction promotes the organisation of intimate cell-cell connections that involve cytoskeleton rearrangement to enable effector function and clearance of the target cell. This is key for the asymmetric transport and mobilisation of lytic granules to the cell-cell contact, promoting directed secretion of lytic mediators such as granzymes and perforin. Mitochondria play a role in regulating CTL function by controlling processes such as calcium flux, providing the necessary energy through oxidative phosphorylation, and its own protein translation on 70S ribosomes. However, the effect of acute inhibition of cytosolic translation in the rapid response after TCR has not been studied in mature CTLs. Here, we investigated the importance of cytosolic protein synthesis in human CTLs after early TCR activation and CD28 co-stimulation for the dynamic reorganisation of the cytoskeleton, mitochondria, and lytic granules through short-term chemical inhibition of 80S ribosomes by cycloheximide and 80S and 70S by puromycin. We observed that eukaryotic ribosome function is required to allow proper asymmetric reorganisation of the tubulin cytoskeleton and mitochondria and mTOR pathway activation early upon TCR activation in human primary CTLs. Cytosolic protein translation is required to increase glucose metabolism and degranulation capacity upon TCR activation and thus to regulate the full effector function of human CTLs.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-12-03
2024
2024-01-01
2024
2024-01-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/25848
url https://hdl.handle.net/20.500.12105/25848
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES S2022 BMD-7209-INTEGRAMUNE-CM
ES LCF PR 52430018
ES MCIN AEI 501100011033
ES PID2022–141895OB-I00 Not available
ES PID2021‐127899OB‐I00 Not available
ES CNS2023–144841 Not available
ES RYC2018–024374-I Not available
ES PI22 01759
ES PI22 01759
ES PMPTA22 00090-BIOCARDIOTOX
ES PI22 01542
ES 2022‐C23.I01.P03.S0020000003 Not available
ES PEJ-2021-TL BMD-21204
ES CPP2021–008385 Not available
ES PRE2021–097478 Not available
ES CM22 00076
ES MICIN AEI 501100011033
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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