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

• Published in: PloS one Vol. 10; no. 9; p. e0137556
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.09.2015; 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; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0137556

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.