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CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division

Immune responses are efficient because the rare antigen-specific naïve cells are able to proliferate extensively and accumulate upon antigen stimulation. Moreover, differentiation into memory cells actually increases T cell accumulation, indicating improved productive division in secondary immune re...

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Autores principales: Galgano, Alessia, Barinov, Aleksandr, Vasseur, Florence, de Villartay, Jean-Pierre, Rocha, Benedita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613136/
https://www.ncbi.nlm.nih.gov/pubmed/26485718
http://dx.doi.org/10.1371/journal.pone.0140849
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author Galgano, Alessia
Barinov, Aleksandr
Vasseur, Florence
de Villartay, Jean-Pierre
Rocha, Benedita
author_facet Galgano, Alessia
Barinov, Aleksandr
Vasseur, Florence
de Villartay, Jean-Pierre
Rocha, Benedita
author_sort Galgano, Alessia
collection PubMed
description Immune responses are efficient because the rare antigen-specific naïve cells are able to proliferate extensively and accumulate upon antigen stimulation. Moreover, differentiation into memory cells actually increases T cell accumulation, indicating improved productive division in secondary immune responses. These properties raise an important paradox: how T cells may survive the DNA lesions necessarily induced during their extensive division without undergoing transformation. We here present the first data addressing the DNA damage responses (DDRs) of CD8 T cells in vivo during exponential expansion in primary and secondary responses in mice. We show that during exponential division CD8 T cells engage unique DDRs, which are not present in other exponentially dividing cells, in T lymphocytes after UV or X irradiation or in non-metastatic tumor cells. While in other cell types a single DDR pathway is affected, all DDR pathways and cell cycle checkpoints are affected in dividing CD8 T cells. All DDR pathways collapse in secondary responses in the absence of CD4 help. CD8 T cells are driven to compulsive suicidal divisions preventing the propagation of DNA lesions. In contrast, in the presence of CD4 help all the DDR pathways are up regulated, resembling those present in metastatic tumors. However, this up regulation is present only during the expansion phase; i.e., their dependence on antigen stimulation prevents CD8 transformation. These results explain how CD8 T cells maintain genome integrity in spite of their extensive division, and highlight the fundamental role of DDRs in the efficiency of CD8 immune responses.
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spelling pubmed-46131362015-10-29 CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division Galgano, Alessia Barinov, Aleksandr Vasseur, Florence de Villartay, Jean-Pierre Rocha, Benedita PLoS One Research Article Immune responses are efficient because the rare antigen-specific naïve cells are able to proliferate extensively and accumulate upon antigen stimulation. Moreover, differentiation into memory cells actually increases T cell accumulation, indicating improved productive division in secondary immune responses. These properties raise an important paradox: how T cells may survive the DNA lesions necessarily induced during their extensive division without undergoing transformation. We here present the first data addressing the DNA damage responses (DDRs) of CD8 T cells in vivo during exponential expansion in primary and secondary responses in mice. We show that during exponential division CD8 T cells engage unique DDRs, which are not present in other exponentially dividing cells, in T lymphocytes after UV or X irradiation or in non-metastatic tumor cells. While in other cell types a single DDR pathway is affected, all DDR pathways and cell cycle checkpoints are affected in dividing CD8 T cells. All DDR pathways collapse in secondary responses in the absence of CD4 help. CD8 T cells are driven to compulsive suicidal divisions preventing the propagation of DNA lesions. In contrast, in the presence of CD4 help all the DDR pathways are up regulated, resembling those present in metastatic tumors. However, this up regulation is present only during the expansion phase; i.e., their dependence on antigen stimulation prevents CD8 transformation. These results explain how CD8 T cells maintain genome integrity in spite of their extensive division, and highlight the fundamental role of DDRs in the efficiency of CD8 immune responses. Public Library of Science 2015-10-20 /pmc/articles/PMC4613136/ /pubmed/26485718 http://dx.doi.org/10.1371/journal.pone.0140849 Text en © 2015 Galgano et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Galgano, Alessia
Barinov, Aleksandr
Vasseur, Florence
de Villartay, Jean-Pierre
Rocha, Benedita
CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division
title CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division
title_full CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division
title_fullStr CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division
title_full_unstemmed CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division
title_short CD8 Memory Cells Develop Unique DNA Repair Mechanisms Favoring Productive Division
title_sort cd8 memory cells develop unique dna repair mechanisms favoring productive division
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613136/
https://www.ncbi.nlm.nih.gov/pubmed/26485718
http://dx.doi.org/10.1371/journal.pone.0140849
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