Prostaglandin E2 Promotes Features of Replicative Senescence in Chronically Activated Human CD8+ T Cells

Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known a...

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Published in:	PloS one Vol. 9; no. 6; p. e99432
Main Authors:	Chou, Jennifer P., Ramirez, Christina M., Ryba, Danielle M., Koduri, Megha P., Effros, Rita B.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 11.06.2014 Public Library of Science (PLoS)
Subjects:	Acquired immune deficiency syndrome Aging AIDS Antigens Base Sequence Biology and Life Sciences Cancer CD28 antigen CD4 antigen CD8 antigen CD8-Positive T-Lymphocytes - cytology CD8-Positive T-Lymphocytes - metabolism Cell activation Cell cycle Cell Cycle - genetics Cell growth Cell survival Cellular Senescence Chronic infection Cyclic AMP - metabolism Cyclooxygenase-2 Cytokines Cytotoxicity Dinoprostone - physiology DNA Primers Feedback loops Flow Cytometry Gene expression Genes, p16 HIV Human immunodeficiency virus Humans Immune system Immunomodulation Infections Laboratories Lymphocyte Activation Lymphocytes Lymphocytes T Medicine Negative feedback Oxidative stress Oxygen Pathology Polymerase Chain Reaction Prostaglandin E2 Reactive oxygen species Reactive Oxygen Species - metabolism Senescence Telomerase Transcription, Genetic Tumor cells Los Angeles California United States > US California
ISSN:	1932-6203, 1932-6203
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Abstract	Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.
AbstractList	Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect. Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.
Author	Ramirez, Christina M. Ryba, Danielle M. Chou, Jennifer P. Koduri, Megha P. Effros, Rita B.
AuthorAffiliation	New York University, United States of America 3 Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America 2 UCLA AIDS Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America 1 Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
AuthorAffiliation_xml	– name: 3 Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America – name: New York University, United States of America – name: 1 Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America – name: 2 UCLA AIDS Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
Author_xml	– sequence: 1 givenname: Jennifer P. surname: Chou fullname: Chou, Jennifer P. – sequence: 2 givenname: Christina M. surname: Ramirez fullname: Ramirez, Christina M. – sequence: 3 givenname: Danielle M. surname: Ryba fullname: Ryba, Danielle M. – sequence: 4 givenname: Megha P. surname: Koduri fullname: Koduri, Megha P. – sequence: 5 givenname: Rita B. surname: Effros fullname: Effros, Rita B.
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Copyright	2014 Chou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2014 Chou et al 2014 Chou et al
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: JPC RBE. Performed the experiments: JPC DMR MPK. Analyzed the data: JPC CMR. Contributed reagents/materials/analysis tools: JPC RBE. Wrote the paper: JPC RBE. Competing Interests: The authors have declared that no competing interests exist.
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SubjectTerms	Acquired immune deficiency syndrome Aging AIDS Antigens Base Sequence Biology and Life Sciences Cancer CD28 antigen CD4 antigen CD8 antigen CD8-Positive T-Lymphocytes - cytology CD8-Positive T-Lymphocytes - metabolism Cell activation Cell cycle Cell Cycle - genetics Cell growth Cell survival Cellular Senescence Chronic infection Cyclic AMP - metabolism Cyclooxygenase-2 Cytokines Cytotoxicity Dinoprostone - physiology DNA Primers Feedback loops Flow Cytometry Gene expression Genes, p16 HIV Human immunodeficiency virus Humans Immune system Immunomodulation Infections Laboratories Lymphocyte Activation Lymphocytes Lymphocytes T Medicine Negative feedback Oxidative stress Oxygen Pathology Polymerase Chain Reaction Prostaglandin E2 Reactive oxygen species Reactive Oxygen Species - metabolism Senescence Telomerase Transcription, Genetic Tumor cells
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Title	Prostaglandin E2 Promotes Features of Replicative Senescence in Chronically Activated Human CD8+ T Cells
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