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EIF4E-dependent Translational Control of Gene Expression in CD4+ T Cell Subsets

Lei Zheng

出版	McGill University Libraries, 2013
URL	http://books.google.com.hk/books?id=MsXhjgEACAAJ&hl=&source=gbs_api

註釋

"Regulatory T (Treg) cells are important to maintain immune tolerance and homeostasis. Previous genome-wide transcriptional profiles have defined canonical signatures of Treg cells that distinguish them from effector T (Teff) cells. However, compelling evidence shows that changes in total mRNA levels do not always correlate with the protein levels due to post-transcriptional regulation. Our laboratory recently has performed the first genome-wide study on translational control of gene expression in primary CD4+ T cell subsets, and eukaryotic translation initiation factor 4E (eIF4E) is found to be translationally suppressed in activated Treg cells compared to activated Teff cells. We also showed that differential eIF4E levels in CD4+ T cell subsets correlated with translation of eIF4E-sensitive cell cycle-related mRNAs, and modulated proliferation and Foxp3 expression in activated CD4+ T cells. Thus, CD4+ T cell subsets exhibit specific translational programs that orchestrate expression of genes which play important roles in the regulation of fundamental cellular processes in CD4+ T cells lineage commitment, genetic programming and function. In this study, we hypothesized that differential expression of eIF4E impacts proliferative and cytokine responses in T cells. We first show that shRNA knockdown of eIF4E dramatically reduces CD4+ T cell proliferation and inflammatory cytokine secretion. As eIF4E activity is directly repressed by the eIF4E-binding proteins (4E-BPs), we hypothesized that CD4+ T cell responses may be skewed in 4E-BP1/2 deficient mouse model. Interestingly, 4E-BP1/2 deficient T cells are not enhanced in their proliferative response following activation, and 4E-BP1/2 deficiency does not abrogate the suppressive function of Treg cells. Moreover, Teff cells lacking 4E-BP1/2 are less sensitive to TGF-b-mediated induction of Treg cells, although rapamycin-mediated Treg induction is not abolished. Collectively, our findings demonstrate that eIF4E could regulate some CD4+ T cell responses in a 4E-BPs-dependent or -independent manner. Specific targeting of eIF4E prominently affects the T cell functional properties, which could open a new era for therapeutic treatment of some autoimmune disease."--