Transcriptomic and T-cell receptor profiling of Treg cells from lymphoid and vascular tissues
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ABSTRACT:
PROVIDER: PRJNA496072 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ Treg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promotes Treg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven Treg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident Treg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.
2024-01-24 | PXD048248 | Pride
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.
2017-08-28 | GSE98263 | GEO
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.
2017-08-28 | GSE98262 | GEO
Project description:Regulatory T (Treg) cells maintain self-tolerance in lymphoid tissues, and specialized Treg cells accumulate and perform homeostasis and regenerative functions in non-lymphoid tissues. A common differentiation pathway of homeostasis-promoting Treg cells in non-lymphoid tissues from a putative precursor remains elusive. By using novel reporter mice and single-cell RNA-sequencing, we identified precursor stages of the IL-33 receptor ST2-expressing non-lymphoid tissue Treg population in spleen and lymph nodes. Molecular profiling of these precursors versus mature tissue Treg cells revealed their sequence of differentiation on a single-cell level. Global chromatin profiling of non-lymphoid tissue Treg cells and progenitor populations revealed a stepwise acquirement of open chromatin accessibility at tissue Treg genes. Mechanistically, we identified and validated the basic leucine zipper transcription factor, ATF-like (Batf) as a driver of the molecular tissue Treg program. Understanding this tissue program will help to harness regenerative properties of tissue Treg cells for therapy.
2020-01-01 | GSE130879 | GEO
Project description:Regulatory T (Treg) cells maintain self-tolerance in lymphoid tissues, and specialized Treg cells accumulate and perform homeostasis and regenerative functions in non-lymphoid tissues. A common differentiation pathway of homeostasis-promoting Treg cells in non-lymphoid tissues from a putative precursor remains elusive. By using novel reporter mice and single-cell RNA-sequencing, we identified precursor stages of the IL-33 receptor ST2-expressing non-lymphoid tissue Treg population in spleen and lymph nodes. Molecular profiling of these precursors versus mature tissue Treg cells revealed their sequence of differentiation on a single-cell level. Global chromatin profiling of non-lymphoid tissue Treg cells and progenitor populations revealed a stepwise acquirement of open chromatin accessibility at tissue Treg genes. Mechanistically, we identified and validated the basic leucine zipper transcription factor, ATF-like (Batf) as a driver of the molecular tissue Treg program. Understanding this tissue program will help to harness regenerative properties of tissue Treg cells for therapy.
2020-01-01 | GSE130875 | GEO
Project description:Regulatory T (Treg) cells maintain self-tolerance in lymphoid tissues, and specialized Treg cells accumulate and perform homeostasis and regenerative functions in non-lymphoid tissues. A common differentiation pathway of homeostasis-promoting Treg cells in non-lymphoid tissues from a putative precursor remains elusive. By using novel reporter mice and single-cell RNA-sequencing, we identified precursor stages of the IL-33 receptor ST2-expressing non-lymphoid tissue Treg population in spleen and lymph nodes. Molecular profiling of these precursors versus mature tissue Treg cells revealed their sequence of differentiation on a single-cell level. Global chromatin profiling of non-lymphoid tissue Treg cells and progenitor populations revealed a stepwise acquirement of open chromatin accessibility at tissue Treg genes. Mechanistically, we identified and validated the basic leucine zipper transcription factor, ATF-like (Batf) as a driver of the molecular tissue Treg program. Understanding this tissue program will help to harness regenerative properties of tissue Treg cells for therapy.
2020-01-01 | GSE130825 | GEO
Project description:Regulatory T (Treg) cells maintain self-tolerance in lymphoid tissues, and specialized Treg cells accumulate and perform homeostasis and regenerative functions in non-lymphoid tissues. A common differentiation pathway of homeostasis-promoting Treg cells in non-lymphoid tissues from a putative precursor remains elusive. By using novel reporter mice and single-cell RNA-sequencing, we identified precursor stages of the IL-33 receptor ST2-expressing non-lymphoid tissue Treg population in spleen and lymph nodes. Molecular profiling of these precursors versus mature tissue Treg cells revealed their sequence of differentiation on a single-cell level. Global chromatin profiling of non-lymphoid tissue Treg cells and progenitor populations revealed a stepwise acquirement of open chromatin accessibility at tissue Treg genes. Mechanistically, we identified and validated the basic leucine zipper transcription factor, ATF-like (Batf) as a driver of the molecular tissue Treg program. Understanding this tissue program will help to harness regenerative properties of tissue Treg cells for therapy.
2020-01-01 | GSE130842 | GEO
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.
2018-09-25 | GSE112731 | GEO
Project description:Non-lymphoid tissues (NLTs) harbour a pool of adaptive immune cells distinct from their counterparts in lymphoid tissues, and their development and phenotype remains largely unexplored. We used scRNA-seq to survey CD4+ T regulatory (Treg) and memory T (Tmem) cells in spleen, lymph nodes, skin and colon in an unbiased way, in mouse. This cross-tissues comparison allows us to obtain marker genes for immune populations in specific locations, as well as examine each population's heterogeneity. Additionally, a continuous phenotype of Treg migration can be modelled from the mouse data, unravelling the transcriptional stages through which these cells transition between tissues.
2019-05-20 | E-MTAB-7311 | biostudies-arrayexpress
Project description:Non-lymphoid tissues (NLTs) harbour a pool of adaptive immune cells distinct from their counterparts in lymphoid tissues, and their development and phenotype remains largely unexplored. We used scRNA-seq to survey CD4+ T regulatory (Treg) and memory T (Tmem) cells in spleen, lymph nodes, skin and colon in an unbiased way, in mouse and human. This cross-tissues, cross-species comparison allows us to obtain marker genes for immune populations in specific locations with likely relevance for human studies. Additionally, a continuous phenotype of Treg migration can be modelled from the mouse data, unravelling the transcriptional stages through which these cells transition between tissues.
2018-12-31 | E-MTAB-6072 | biostudies-arrayexpress