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Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy
Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a ‘cytokine storm’, a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draini...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606384/ https://www.ncbi.nlm.nih.gov/pubmed/23533579 http://dx.doi.org/10.1371/journal.pone.0058033 |
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author | Matheu, Melanie P. Teijaro, John R. Walsh, Kevin B. Greenberg, Milton L. Marsolais, David Parker, Ian Rosen, Hugh Oldstone, Michael B A. Cahalan, Michael D. |
author_facet | Matheu, Melanie P. Teijaro, John R. Walsh, Kevin B. Greenberg, Milton L. Marsolais, David Parker, Ian Rosen, Hugh Oldstone, Michael B A. Cahalan, Michael D. |
author_sort | Matheu, Melanie P. |
collection | PubMed |
description | Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a ‘cytokine storm’, a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draining lymph node, leading to expansion of virus-specific effector cells. Using two-photon microscopy, we imaged the dynamics of dendritic cells (DC) and virus-specific eGFP(+)CD8(+) T cells in the lungs and draining mediastinal lymph nodes during the first two weeks following influenza infection. Three distinct phases of T cell and CD11c(+) DC behavior were revealed: 1) Priming, facilitated by the arrival of lung DCs in the lymph node and characterized by antigen recognition and expansion of antigen-specific CD8(+) T cells; asymmetric T cell division in contact with DCs was frequently observed. 2) Clearance, during which DCs re-populate the lung and T cells leave the draining lymph node and re-enter the lung tissue where enlarged, motile T cells come into contact with DCs and form long-lived interactions. 3) Maintenance, characterized by T-cell scanning of the lung tissue and dissociation from local antigen presenting cells; the T cells spend less time in association with DCs and migrate rapidly on collagen. A single dose of a sphingosine-1-phosphate receptor agonist, AAL-R, sufficient to suppress influenza-induced cytokine-storm, altered T cell and DC behavior during influenza clearance, delaying T cell division, cellular infiltration in the lung, and suppressing T-DC interactions in the lung. Our results provide a detailed description of T cell and DC choreography and dynamics in the lymph node and the lung during influenza infection. In addition, we suggest that phase lags in T cell and DC dynamics induced by targeting S1P receptors in vivo may attenuate the intensity of the immune response and can be manipulated for therapeutic benefit. |
format | Online Article Text |
id | pubmed-3606384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36063842013-03-26 Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy Matheu, Melanie P. Teijaro, John R. Walsh, Kevin B. Greenberg, Milton L. Marsolais, David Parker, Ian Rosen, Hugh Oldstone, Michael B A. Cahalan, Michael D. PLoS One Research Article Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a ‘cytokine storm’, a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draining lymph node, leading to expansion of virus-specific effector cells. Using two-photon microscopy, we imaged the dynamics of dendritic cells (DC) and virus-specific eGFP(+)CD8(+) T cells in the lungs and draining mediastinal lymph nodes during the first two weeks following influenza infection. Three distinct phases of T cell and CD11c(+) DC behavior were revealed: 1) Priming, facilitated by the arrival of lung DCs in the lymph node and characterized by antigen recognition and expansion of antigen-specific CD8(+) T cells; asymmetric T cell division in contact with DCs was frequently observed. 2) Clearance, during which DCs re-populate the lung and T cells leave the draining lymph node and re-enter the lung tissue where enlarged, motile T cells come into contact with DCs and form long-lived interactions. 3) Maintenance, characterized by T-cell scanning of the lung tissue and dissociation from local antigen presenting cells; the T cells spend less time in association with DCs and migrate rapidly on collagen. A single dose of a sphingosine-1-phosphate receptor agonist, AAL-R, sufficient to suppress influenza-induced cytokine-storm, altered T cell and DC behavior during influenza clearance, delaying T cell division, cellular infiltration in the lung, and suppressing T-DC interactions in the lung. Our results provide a detailed description of T cell and DC choreography and dynamics in the lymph node and the lung during influenza infection. In addition, we suggest that phase lags in T cell and DC dynamics induced by targeting S1P receptors in vivo may attenuate the intensity of the immune response and can be manipulated for therapeutic benefit. Public Library of Science 2013-03-22 /pmc/articles/PMC3606384/ /pubmed/23533579 http://dx.doi.org/10.1371/journal.pone.0058033 Text en © 2013 Matheu 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 Matheu, Melanie P. Teijaro, John R. Walsh, Kevin B. Greenberg, Milton L. Marsolais, David Parker, Ian Rosen, Hugh Oldstone, Michael B A. Cahalan, Michael D. Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy |
title | Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy |
title_full | Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy |
title_fullStr | Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy |
title_full_unstemmed | Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy |
title_short | Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy |
title_sort | three phases of cd8 t cell response in the lung following h1n1 influenza infection and sphingosine 1 phosphate agonist therapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606384/ https://www.ncbi.nlm.nih.gov/pubmed/23533579 http://dx.doi.org/10.1371/journal.pone.0058033 |
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