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Altered microRNA expression in individuals at high risk of type 1 diabetes

ABSTRACT: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic insulin-producing β cells. CD4+ T cells are integral to the pathogenesis of T1D, but biomarkers that define their pathogenic status in T1D are lacking. miRNAs have essential functions in a wide range of tissues/organs, including the immune system. We reasoned that CD4+ T cells from individuals at high risk for T1D (pre-T1D) might be distinguished by an miRNA signature. We sorted CD4+ T cells from 9 healthy and 7 pre-T1D individuals into 6 subsets, namely naïve, resting regulatory (rTreg), activated regulatory (aTreg), transitional memory (Ttm), central memory (Tcm) and effector memory (Tem) cells, and then compared miRNA profiles between these subsets and between pre-T1D and healthy individuals by deep sequencing. Differential expression of miRNAs was detected in each of the CD4+ T cell subsets. For example, expression of miRNAs that induce apoptosis (miR-15a) or FOXP3 instability (miR-31) was increased in rTreg and aTreg cells, respectively, in pre-T1D individuals, whereas miR-150 was increased in Tem cells of pre-T1D individuals. Importantly, increased miR-150 expression could be detected by qRT-PCR in total CD4+ T and PBMCs of pre-T1D individuals. Consistent with it being a marker of pathogenic CD4+ T cells, we showed that miR-150 regulates IFN-γ production in mouse CD4+ T cells. Thus, comprehensive profiling identifies miRNA profiles that not only distinguish CD4+ T cell subsets but also discriminate individuals with preclinical T1D. The ability to detect differentially expressed miRNAs in total CD4+ T cells or PBMCs should facilitate clinical application of miRNAs as biomarkers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44639 | GEO | 2015/12/31

SECONDARY ACCESSION(S): PRJNA190702

REPOSITORIES: GEO

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Project 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, 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. MicroRNA profiling was performed in eight T cell subsets: CD4 naive (CD3+CD4+CD45RO-), CD8 naive (CD3+CD4-CD45RO-), CD4 memory (CD3+CD4+CD45RO+) and CD8 memory (CD3+CD4-CD45RO+) T cells derived from 5 healthy young and 5 healthy old participants.

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Altered microRNA expression in individuals at high risk of type 1 diabetes

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