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.
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.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Nato
authors.initials: N
authors.lastname: Teteloshvili
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Kluiver
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Kornelis S M
authors.initials: KS
authors.lastname: van der Geest
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Roelof Jan
authors.initials: RJ
authors.lastname: van der Lei
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pytrick
authors.initials: P
authors.lastname: Jellema
authors.affiliation: Department of Internal Medicine II, Centre for Medical Research, University of Tübingen, Tübingen, Germany; School of Science and Technology, Nottingham Trent University, Nottingham, United KIngdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brouwer
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kroesen
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D059467:Transcriptome
chemical_list: D017493:Leukocyte Common Antigens; D035683:MicroRNAs; C524940:MIRN21 microRNA, human; C525067:MIR223, human