Molecular diversification of regulatory T cells in non-lymphoid tissues
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA448878 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6945570.fastq.gz | Fastqsanger.gz | |||
| SRR6945570_1.fastq.gz | Fastqsanger.gz | |||
| SRR6945570_2.fastq.gz | Fastqsanger.gz | |||
| SRR6945571.fastq.gz | Fastqsanger.gz | |||
| SRR6945571_1.fastq.gz | Fastqsanger.gz |
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Project description:Foxp3+CD4+ regulatory T (Treg) cells accumulate in certain non-lymphoid tissues, where they control diverse aspects of organ homeostasis, partly via a direct impact on neighboring non-immune cells. Populations of tissue-Tregs, as they have been termed, have transcriptomes distinct from those of their counterparts in lymphoid organs and other non-lymphoid tissues. Exploiting recent advances in profiling the chromatin accessibility and gene expression of rare cell populations, we examined the diversification of Tregs in visceral-adipose tissue, skeletal muscle and the colon vis-à-vis lymphoid organs from the same individuals. The unique transcriptomes of the various tissue-Treg populations reflected layering of tissue-restricted stretches of accessibility over a “primed” landscape of sites already open in the spleen, where they were tagged by super-enhancers and “bivalent” histone marks of transcriptional activation and repression. Tissue-restricted chromatin accessibility and gene expression correlated with the binding motifs of a small number of transcription-factor (TF) families repeatedly enriched across the various non-lymphoid tissues. However, a bioinformatically and experimentally validated transcriptional network constructed using a combination of chromatin-accessibility and single-cell transcriptomic data predicted usage of different TF-family members in the different tissues. The network analysis also revealed that tissue-restricted and ubiquitously acting TFs were integrated into feed-forward loops to enforce tissue-specific gene expression in non-lymphoid-tissue Treg cells. Overall, this study provides a framework for understanding the epigenetic dynamics of T cells operating in non-lymphoid tissues, which should inform strategies for specifically targeting them.
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Project description:The TNF receptor super family - NF-κB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues
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Project description:Foxp3+CD4+ regulatory T cells (Tregs) accumulate in certain nonlymphoid tissues, where they control diverse aspects of organ homeostasis. Populations of tissue Tregs, as they have been termed, have transcriptomes distinct from those of their counterparts in lymphoid organs and other nonlymphoid tissues. We examined the diversification of Tregs in visceral adipose tissue, skeletal muscle, and the colon vis-à-vis lymphoid organs from the same individuals. The unique transcriptomes of the various tissue Treg populations resulted from layering of tissue-restricted open chromatin regions over regions already open in the spleen, the latter tagged by super-enhancers and particular histone marks. The binding motifs for a small number of transcription factor (TF) families were repeatedly enriched within the accessible chromatin stretches of Tregs in the three nonlymphoid tissues. However, a bioinformatically and experimentally validated transcriptional network, constructed by integrating chromatin accessibility and single-cell transcriptomic data, predicted reliance on different TF family members in the different tissues. The network analysis also revealed that tissue-restricted and broadly acting TFs were integrated into feed-forward loops to enforce tissue-specific gene expression in nonlymphoid-tissue Tregs. Overall, this study provides a framework for understanding the epigenetic dynamics of T cells operating in nonlymphoid tissues, which should inform strategies for specifically targeting them.
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Project description:After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery resulting in the generation of effector (e)Treg cells, a process dependent on TCR signaling and the transcription factor IRF4. Here we show tumor necrosis factor receptor super family (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA and induced expansion and survival of eTreg cells in lymphoid and non-lymphoid tissues, including RORγt+ resident Treg cells in the small intestine. RelA regulated basic cellular processes in Treg cells, including cell survival and proliferation in response to TNFRSF signaling, but was not required for IRF4 expression or DNA binding, indicating that both pathways operate independently. Importantly, a similar pathway appeared to be active in humans, as patients with a point mutation in NF-κB1, a binding partner of RelA, had severely compromised Treg cells. Therefore, although TCR signaling is essential for eTreg cell differentiation, the TNFRSF-NF-κB axis was additionally required in a non-redundant manner to maintain the pool of eTreg cells.
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