Transcriptional Heterogeneity, Identity and Stability of Regulatory T Cells
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CitationPuyraimond-Zemmour, David. 2017. Transcriptional Heterogeneity, Identity and Stability of Regulatory T Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractCD4+ FoxP3+ regulatory T cells (Tregs) are a considerably diverse, yet stable cell type. These two properties are essential for Tregs to maintain immune and tissue homeostasis in the different environments and target cells they need to regulate. In order to study what constitutes their transcriptional identity and the extent of their heterogeneity, we sequenced the transcriptome of thousands of single Treg and Tconv (CD4+ FoxP3- T cells) cells isolated from lymphoid and non-lymphoid organs (spleen, visceral adipose tissue, colon and skeletal muscle). The transcriptome of Tregs is modular and composed of a small set of common FoxP3-dependent transcripts, shared by all Tregs but absent in Tconvs, onto which additional programs are added less uniformly across Tregs. Some of these programs are common with Tconvs, which results in convergent Treg-Tconv states mainly related to activation. Lymphoid and tissue Tregs show unappreciated heterogeneity within each organ, influenced by different levels of TCR activation, TCR sequences or the microbiota. Taking advantage of the inter-cellular variability in gene expression between single Treg cells across tissues, we uncovered that tissue-Treg transcriptional regulation is modular, dynamic and regulated by a combination of ubiquitous and tissue-specific transcription factors. While mining the transcriptional landscape of Tregs, we discovered a novel long noncoding RNA, Flicr ( Foxp3 -regulating long intergenic noncoding RNA), in the Foxp3 locus. Flicr is specifically expressed in human and mouse Tregs and acts as a negative regulator that fine-tunes Foxp3 expression in a subset of Tregs. Like many lncRNAs, Flicr ’s molecular effects are subtle, but by curtailing Treg activity, Flicr markedly promotes autoimmune diabetes. Overall, this study provides a transcriptional framework to understand Treg heterogeneity and the underlying mechanisms of tissue diversification. It also illustrates the emerging role of long noncoding RNAs as potent regulators of immune functions.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42061508
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