Age-Associated Differences in MiRNA Signatures Are Restricted to CD45RO Negative T Cells and Are Associated with Changes in the Cellular Composition, Activation and Cellular Ageing
MicroRNAs (miRNAs) have emerged as important players in the regulation of T-cell functionality. However, comprehensive insight into the extent of age-related miRNA changes in T cells is lacking. We established miRNA expression patterns of CD45RO- naïve and CD45RO+ memory T-cell subsets isolated from...
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| Veröffentlicht in: | PloS one 2015-09, Vol.10 (9), p.e0137556-e0137556 |
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| creator | Teteloshvili, Nato Kluiver, Joost van der Geest, Kornelis S M van der Lei, Roelof Jan Jellema, Pytrick Pawelec, Graham Brouwer, Elisabeth Kroesen, Bart-Jan Boots, Annemieke M H van den Berg, Anke |
| description | MicroRNAs (miRNAs) have emerged as important players in the regulation of T-cell functionality. However, comprehensive insight into the extent of age-related miRNA changes in T cells is lacking. We established miRNA expression patterns of CD45RO- naïve and CD45RO+ memory T-cell subsets isolated from peripheral blood cells from young and elderly individuals. Unsupervised clustering of the miRNA expression data revealed an age-related clustering in the CD45RO- T cells, while CD45RO+ T cells clustered based on expression of CD4 and CD8. Seventeen miRNAs showed an at least 2-fold up- or downregulation in CD45RO- T cells obtained from young as compared to old donors. Validation on the same and independent samples revealed a statistically significant age-related upregulation of miR-21, miR-223 and miR-15a. In a T-cell subset analysis focusing on known age-related phenotypic changes, we showed significantly higher miR-21 and miR-223 levels in CD8+CD45RO-CCR7- TEMRA compared to CD45RO-CCR7+ TNAIVE-cells. Moreover, miR-21 but not miR-223 levels were significantly increased in CD45RO-CD31- post-thymic TNAIVE cells as compared to thymic CD45RO-CD31+ TNAIVE cells. Upon activation of CD45RO- TNAIVE cells we observed a significant induction of miR-21 especially in CD4+ T cells, while miR-223 levels significantly decreased only in CD4+ T cells. Besides composition and activation-induced changes, we showed a borderline significant increase in miR-21 levels upon an increasing number of population doublings in CD4+ T-cell clones. Together, our results show that ageing related changes in miRNA expression are dominant in the CD45RO- T-cell compartment. The differential expression patterns can be explained by age related changes in T-cell composition, i.e. accumulation of CD8+ TEMRA and CD4+ post-thymic expanded CD31- T cells and by cellular ageing, as demonstrated in a longitudinal clonal culture model. |
| doi_str_mv | 10.1371/journal.pone.0137556 |
| format | Article |
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However, comprehensive insight into the extent of age-related miRNA changes in T cells is lacking. We established miRNA expression patterns of CD45RO- naïve and CD45RO+ memory T-cell subsets isolated from peripheral blood cells from young and elderly individuals. Unsupervised clustering of the miRNA expression data revealed an age-related clustering in the CD45RO- T cells, while CD45RO+ T cells clustered based on expression of CD4 and CD8. Seventeen miRNAs showed an at least 2-fold up- or downregulation in CD45RO- T cells obtained from young as compared to old donors. Validation on the same and independent samples revealed a statistically significant age-related upregulation of miR-21, miR-223 and miR-15a. In a T-cell subset analysis focusing on known age-related phenotypic changes, we showed significantly higher miR-21 and miR-223 levels in CD8+CD45RO-CCR7- TEMRA compared to CD45RO-CCR7+ TNAIVE-cells. Moreover, miR-21 but not miR-223 levels were significantly increased in CD45RO-CD31- post-thymic TNAIVE cells as compared to thymic CD45RO-CD31+ TNAIVE cells. Upon activation of CD45RO- TNAIVE cells we observed a significant induction of miR-21 especially in CD4+ T cells, while miR-223 levels significantly decreased only in CD4+ T cells. Besides composition and activation-induced changes, we showed a borderline significant increase in miR-21 levels upon an increasing number of population doublings in CD4+ T-cell clones. Together, our results show that ageing related changes in miRNA expression are dominant in the CD45RO- T-cell compartment. The differential expression patterns can be explained by age related changes in T-cell composition, i.e. accumulation of CD8+ TEMRA and CD4+ post-thymic expanded CD31- T cells and by cellular ageing, as demonstrated in a longitudinal clonal culture model.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0137556</identifier><identifier>PMID: 26360056</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Age ; Aged ; Aged, 80 and over ; Aging ; Aging (Biology) ; Analysis ; Apoptosis ; Biology ; Blood cells ; CC chemokine receptors ; CCR7 protein ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Cell activation ; Cell culture ; Cells, Cultured ; Cellular Senescence ; Cloning ; Clustering ; Comparative analysis ; Female ; Geriatrics ; Humans ; Immune system ; Immunological memory ; Immunology ; Leukocyte Common Antigens - genetics ; Leukocyte Common Antigens - metabolism ; Lymphocyte Activation ; Lymphocytes ; Lymphocytes T ; Male ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; Middle Aged ; miRNA ; Older people ; Pathology ; Peripheral blood ; Rheumatology ; Senescence ; Statistical analysis ; Statistical methods ; T cells ; Thymus ; Transcriptome</subject><ispartof>PloS one, 2015-09, Vol.10 (9), p.e0137556-e0137556</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Teteloshvili 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.</rights><rights>2015 Teteloshvili et al 2015 Teteloshvili et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-1fa30d53219e14e8ed18b5c6abedfdea9ea815624610fa117a6b54f92313eb7e3</citedby><cites>FETCH-LOGICAL-c692t-1fa30d53219e14e8ed18b5c6abedfdea9ea815624610fa117a6b54f92313eb7e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567287/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567287/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26360056$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mari, Bernard</contributor><creatorcontrib>Teteloshvili, Nato</creatorcontrib><creatorcontrib>Kluiver, Joost</creatorcontrib><creatorcontrib>van der Geest, Kornelis S M</creatorcontrib><creatorcontrib>van der Lei, Roelof Jan</creatorcontrib><creatorcontrib>Jellema, Pytrick</creatorcontrib><creatorcontrib>Pawelec, Graham</creatorcontrib><creatorcontrib>Brouwer, Elisabeth</creatorcontrib><creatorcontrib>Kroesen, Bart-Jan</creatorcontrib><creatorcontrib>Boots, Annemieke M H</creatorcontrib><creatorcontrib>van den Berg, Anke</creatorcontrib><title>Age-Associated Differences in MiRNA Signatures Are Restricted to CD45RO Negative T Cells and Are Associated with Changes in the Cellular Composition, Activation and Cellular Ageing</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>MicroRNAs (miRNAs) have emerged as important players in the regulation of T-cell functionality. However, comprehensive insight into the extent of age-related miRNA changes in T cells is lacking. We established miRNA expression patterns of CD45RO- naïve and CD45RO+ memory T-cell subsets isolated from peripheral blood cells from young and elderly individuals. Unsupervised clustering of the miRNA expression data revealed an age-related clustering in the CD45RO- T cells, while CD45RO+ T cells clustered based on expression of CD4 and CD8. Seventeen miRNAs showed an at least 2-fold up- or downregulation in CD45RO- T cells obtained from young as compared to old donors. Validation on the same and independent samples revealed a statistically significant age-related upregulation of miR-21, miR-223 and miR-15a. In a T-cell subset analysis focusing on known age-related phenotypic changes, we showed significantly higher miR-21 and miR-223 levels in CD8+CD45RO-CCR7- TEMRA compared to CD45RO-CCR7+ TNAIVE-cells. Moreover, miR-21 but not miR-223 levels were significantly increased in CD45RO-CD31- post-thymic TNAIVE cells as compared to thymic CD45RO-CD31+ TNAIVE cells. Upon activation of CD45RO- TNAIVE cells we observed a significant induction of miR-21 especially in CD4+ T cells, while miR-223 levels significantly decreased only in CD4+ T cells. Besides composition and activation-induced changes, we showed a borderline significant increase in miR-21 levels upon an increasing number of population doublings in CD4+ T-cell clones. Together, our results show that ageing related changes in miRNA expression are dominant in the CD45RO- T-cell compartment. The differential expression patterns can be explained by age related changes in T-cell composition, i.e. accumulation of CD8+ TEMRA and CD4+ post-thymic expanded CD31- T cells and by cellular ageing, as demonstrated in a longitudinal clonal culture model.</description><subject>Adult</subject><subject>Age</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aging</subject><subject>Aging (Biology)</subject><subject>Analysis</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Blood cells</subject><subject>CC chemokine receptors</subject><subject>CCR7 protein</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cells, Cultured</subject><subject>Cellular Senescence</subject><subject>Cloning</subject><subject>Clustering</subject><subject>Comparative analysis</subject><subject>Female</subject><subject>Geriatrics</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunological memory</subject><subject>Immunology</subject><subject>Leukocyte Common Antigens - genetics</subject><subject>Leukocyte Common Antigens - metabolism</subject><subject>Lymphocyte Activation</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>Middle Aged</subject><subject>miRNA</subject><subject>Older people</subject><subject>Pathology</subject><subject>Peripheral blood</subject><subject>Rheumatology</subject><subject>Senescence</subject><subject>Statistical analysis</subject><subject>Statistical methods</subject><subject>T cells</subject><subject>Thymus</subject><subject>Transcriptome</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk91u0zAUgCMEYmPwBggsISGQaInt2ElukKKOn0pjk7rBreU4J6mn1C62M-C9eECctptatAuUizgn3_lsH_skyXOcTjHN8ftrOzgj--naGpimMcQYf5Ac45KSCScpfbg3PkqeeH-dpowWnD9OjginPH7x4-RP1cGk8t4qLQM06FS3LTgwCjzSBn3Vi_MKXerOyDC4GKscoAX44LQa8WDR7DRjiwt0Dp0M-gbQFZpB33skTbOh9-Q_dVii2VKabmsPS9jAQy8dmtnV2nodtDXvUKWiS47jjecOiqvVpnuaPGpl7-HZ7n2SfPv08Wr2ZXJ28Xk-q84mipckTHAradowSnAJOIMCGlzUTHFZQ9M2IEuQBWacZBynrcQ4l7xmWVsSiinUOdCT5OXWu-6tF7uCe4FzXJK8KPM8EvMt0Vh5LdZOr6T7LazUYhOwrhPSBa16EIAxrglLVZFnGdRQpwUrcN6UGYE2DqLrw262oV5Bo8AEJ_sD6eEfo5eiszciYzwnxSh4sxM4-2OIhyRW2qtYOmnADpt1E0YIZUVEX_2D3r-7HdXJuAFtWhvnVaNUVBkpKCGc00hN76Hi08BKq3g7Wx3jBwlvDxIiE-BX6OTgvZhfLv6fvfh-yL7eY5cg-7D0th_Ga-QPwWwLKme9d9DeFRmnYmyu22qIsbnErrli2ov9A7pLuu0m-hdIPR9r</recordid><startdate>20150911</startdate><enddate>20150911</enddate><creator>Teteloshvili, Nato</creator><creator>Kluiver, Joost</creator><creator>van der Geest, Kornelis S M</creator><creator>van der Lei, Roelof Jan</creator><creator>Jellema, Pytrick</creator><creator>Pawelec, Graham</creator><creator>Brouwer, Elisabeth</creator><creator>Kroesen, Bart-Jan</creator><creator>Boots, Annemieke M H</creator><creator>van den Berg, Anke</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150911</creationdate><title>Age-Associated Differences in MiRNA Signatures Are Restricted to CD45RO Negative T Cells and Are Associated with Changes in the Cellular Composition, Activation and Cellular Ageing</title><author>Teteloshvili, Nato ; Kluiver, Joost ; van der Geest, Kornelis S M ; van der Lei, Roelof Jan ; Jellema, Pytrick ; Pawelec, Graham ; Brouwer, Elisabeth ; Kroesen, Bart-Jan ; Boots, Annemieke M H ; van den Berg, Anke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-1fa30d53219e14e8ed18b5c6abedfdea9ea815624610fa117a6b54f92313eb7e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Age</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Aging</topic><topic>Aging (Biology)</topic><topic>Analysis</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Blood cells</topic><topic>CC chemokine receptors</topic><topic>CCR7 protein</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Teteloshvili, Nato</au><au>Kluiver, Joost</au><au>van der Geest, Kornelis S M</au><au>van der Lei, Roelof Jan</au><au>Jellema, Pytrick</au><au>Pawelec, Graham</au><au>Brouwer, Elisabeth</au><au>Kroesen, Bart-Jan</au><au>Boots, Annemieke M H</au><au>van den Berg, Anke</au><au>Mari, Bernard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Age-Associated Differences in MiRNA Signatures Are Restricted to CD45RO Negative T Cells and Are Associated with Changes in the Cellular Composition, Activation and Cellular Ageing</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-09-11</date><risdate>2015</risdate><volume>10</volume><issue>9</issue><spage>e0137556</spage><epage>e0137556</epage><pages>e0137556-e0137556</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>MicroRNAs (miRNAs) have emerged as important players in the regulation of T-cell functionality. However, comprehensive insight into the extent of age-related miRNA changes in T cells is lacking. We established miRNA expression patterns of CD45RO- naïve and CD45RO+ memory T-cell subsets isolated from peripheral blood cells from young and elderly individuals. Unsupervised clustering of the miRNA expression data revealed an age-related clustering in the CD45RO- T cells, while CD45RO+ T cells clustered based on expression of CD4 and CD8. Seventeen miRNAs showed an at least 2-fold up- or downregulation in CD45RO- T cells obtained from young as compared to old donors. Validation on the same and independent samples revealed a statistically significant age-related upregulation of miR-21, miR-223 and miR-15a. In a T-cell subset analysis focusing on known age-related phenotypic changes, we showed significantly higher miR-21 and miR-223 levels in CD8+CD45RO-CCR7- TEMRA compared to CD45RO-CCR7+ TNAIVE-cells. Moreover, miR-21 but not miR-223 levels were significantly increased in CD45RO-CD31- post-thymic TNAIVE cells as compared to thymic CD45RO-CD31+ TNAIVE cells. Upon activation of CD45RO- TNAIVE cells we observed a significant induction of miR-21 especially in CD4+ T cells, while miR-223 levels significantly decreased only in CD4+ T cells. Besides composition and activation-induced changes, we showed a borderline significant increase in miR-21 levels upon an increasing number of population doublings in CD4+ T-cell clones. Together, our results show that ageing related changes in miRNA expression are dominant in the CD45RO- T-cell compartment. The differential expression patterns can be explained by age related changes in T-cell composition, i.e. accumulation of CD8+ TEMRA and CD4+ post-thymic expanded CD31- T cells and by cellular ageing, as demonstrated in a longitudinal clonal culture model.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26360056</pmid><doi>10.1371/journal.pone.0137556</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-09, Vol.10 (9), p.e0137556-e0137556 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1719278977 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adult Age Aged Aged, 80 and over Aging Aging (Biology) Analysis Apoptosis Biology Blood cells CC chemokine receptors CCR7 protein CD4 antigen CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell activation Cell culture Cells, Cultured Cellular Senescence Cloning Clustering Comparative analysis Female Geriatrics Humans Immune system Immunological memory Immunology Leukocyte Common Antigens - genetics Leukocyte Common Antigens - metabolism Lymphocyte Activation Lymphocytes Lymphocytes T Male MicroRNA MicroRNAs MicroRNAs - genetics Middle Aged miRNA Older people Pathology Peripheral blood Rheumatology Senescence Statistical analysis Statistical methods T cells Thymus Transcriptome |
| title | Age-Associated Differences in MiRNA Signatures Are Restricted to CD45RO Negative T Cells and Are Associated with Changes in the Cellular Composition, Activation and Cellular Ageing |
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