Abstract
microRN'As are a class of short RNA molecules that mediate post-transcriptional regulation of gene expression thereby controlling cell fate. The importance of microRN'As in normal T helper cell function has been highlighted by recent studies in which T cells that are globally deficient in microRNAs exhibit major abnormalities of homeostasis and differentiation. However the identities of those individual microRNAs that are required for normal T cell function remain unclear, and there is a lack of data regarding the cellular processes that are regulated by microRNAs in T cells.This thesis examines the hypothesis that specific microRNAs are of critical importance for normal T helper cell function and differentiation. microRNA expression was profiled in highly-polarised T helper cell subsets, and analysed in order to detect differentially expressed microRNAs. A candidate microRNA, mir-142, was selected on the basis of these data for further functional analysis. Novel constitutive and conditional mir-I42-deficient mice were generated and systematically analysed for T cell functional defects. mir-142 deficiency was found to profoundly affect T cell homeostasis, with a significant reduction in the size of the peripheral T cell pool and impaired proliferation and survival in vivo. T helper cell differentiation was also affected, with default adoption of a Th1 phenotype and impaired stability of non-Th1 lineages. Analysis of predicted targets revealed that both retinoic acid receptor (RAR)-γ and T -bet are targets of mir-142 that are functionally responsible for these abnormalities. Deficiency of mir-142 in T helper cells was also found to prevent the development of disease in a T cell-mediated colitis model. In summaiy, this work identifies mir-142 as a critically important microRNA for normal T helper cell function and differentiation. Future studies will continue to analyse the function of mir-142 and may investigate this microRNA as a potential therapeutic target in immune-mediated disease.
| Date of Award | 2012 |
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| Original language | English |
| Awarding Institution |
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