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Single-cell Transcriptomic Analysis Reveals Disparate Effector Differentiation Pathways in Human Treg Compartment [Treg_HD]

ABSTRACT: Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve/activated/effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic/functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional/migratory impairments under aGVHD. The findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE175602 | GEO | 2021/05/27

REPOSITORIES: GEO

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Single-cell Transcriptomic Analysis Reveals Disparate Effector Differentiation Pathways in Human Treg Compartment [Treg patients]

Project description:Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve/activated/effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic/functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional/migratory impairments under aGVHD. The findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.

2021-05-27 | GSE175603 | GEO

Whole genome expression analysis of tumor regulatory T cells expressing interleukin-10

Project description:The tumor microenvironment contains high frequencies of inflammatory regulatory T (Treg) cells. These Treg exhibit superior regulatory function compared with those from other environments such as the spleen, partially due to expression of anti-inflammatory interleukin-10. In order to gain insight into the origins and functional roles of different Treg subsets, we used whole genome microarray analysis to characterize tumor IL-10+ and tumor IL-10- Treg subsets obtained from VERT-X reporter mice bearing transplantable tumors, along with total tumor Treg and spleen Treg from FoxP3-EGFP reporter mice. Few genes were found to differ between IL-10+ and IL-10- tumor Treg subsets (29 upregulated, 88 downregulated), suggesting a common origin of each Treg subset. The specific gene expression profile of IL-10+ tumor Treg was associated with the tumor microenvironment and absent from spleen Treg, suggesting it to be driven by components of the inflammatory tumor microenvironment. The IL-10+ tumor Treg gene expression profile displayed upregulation of genes associated with a higher activation state and greater effector function. Pooled MC38 tumor tissue from VERT-X or FoxP3-EGFP reporter mice were used to obtain IL10+ tumor Treg (VERT-X), IL10- tumor Treg (VERT-X) and total tumor Treg (FoxP3-EGFP). Spleens from tumor-free FoxP3-EGFP mice were used for spleen Treg. Three experiments for each population gave a total 12 RNA samples.

2013-08-31 | E-GEOD-49380 | biostudies-arrayexpress

Transcriptional analysis of resting T cells from human blood and skin

Project description:After activation, CD4+ T helper (Th) cells differentiate into functionally specialized populations that coordinate distinct immune responses and protect against different types of pathogens. In humans, these effector and memory Th cell subsets can be readily identified in peripheral blood based on their differential expression of chemokine receptors that govern their homeostatic and inflammatory trafficking. Foxp3+ regulatory T (Treg) cells can also be divided into subsets that phenotypically mirror each of these effector populations, and share expression of key transcription factors and effector cytokines. In this study, we performed comprehensive transcriptional profiling of 11 phenotypically distinct Th and Treg cell subsets sorted from peripheral blood of healthy individuals. Despite their shared phenotypes, we found that mirror Th and Treg subsets were transcriptionally dissimilar, and that Treg cell populations showed limited transcriptional diversity compared to Th cells. We identified core transcriptional signatures shared across all Th and Treg cell populations, and unique signatures that define each of the Th or Treg populations. Finally, we applied these signatures to bulk Th and Treg RNA-seq data and found enrichment of specific Th and Treg cell populations in different human tissues. These results further define the molecular basis for the functional specialization and differentiation of Th and Treg cell populations, and provide a new resource for examining Th and Treg specialization in RNA-seq data.

2020-08-05 | GSE148970 | GEO

RNA-seq of human CD4+ T cell subsets

2020-08-05 | GSE135390 | GEO

Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.

2019-09-02 | PXD011164 | Pride

Gene expression profiles of CD4SP Foxp3GFP-CD25+ Treg precursors and Foxp3GFP-CD25- thymocytes

Project description:We investigated at which stage of maturation commitment to a stable Foxp3-expressing phenotype takes place. We assessed stability of Foxp3 expression in thymic Foxp3+ Treg subsets of different maturity, defined by CD24 expression. Next we compared gene expression profiles of Foxp3+ Treg subsets (+) of different maturity (24lo, 24int, 24hi) and could identify a set of genes that were specifically up or downregulated in Foxp3+ Tregs, but not in Foxp3- conventional T cells, in a maturation-dependent manner. Gene expression of Foxp3+ Treg subsets (+) of different maturity (24lo, 24int, 24hi) compared to their Foxp3- conventional Tcell subsets (-) counterpart.

2013-03-07 | E-GEOD-42021 | biostudies-arrayexpress

The transcriptome analysis of Treg subset

Project description:The transcriptome analysis of WT and Tcf7/Lef1 double knockout (dKO) Treg subset CD4+ Foxp3+ T regulatory (Treg) cells are key players in preventing lethal autoimmunity and deleterious tissue inflammation. To fulfill these roles, Treg cells undergo activation and differentiate processes to acquire diverse functional properties. However, how Treg’s functional specifications are regulated during their differentiation remains poorly understood. Here we show that two TCF/LEF family transcription factors (TFs), TCF1 and LEF1 act redundantly as checkpoint regulators in peripheral Treg homeostatic differentiation and functional subset specification. We find that gradient expression of TCF1 and LEF1 distinguishes Treg cells into three distinct subsets. Sustained expression of TCF1/LEF1 retains Treg at their resting stage. Conversely, conditional knockout of TCF1 and LEF1 promotes the effector-like phenotype in bulk Treg cells, but surprisingly renders the mice susceptible to early onset of systemic autoimmunity. This uncoupling between Treg effector phenotype and their function in suppressing autoimmunity is attributed by two TCF1/LEF1-centered mechanisms. First, the ablation of TCF1 and LEF1 in Treg cells abolishes the generation of T follicular regulatory (Tfr) cells, leading to unrestrained T follicular helper (Tfh) and germinal center B cell responses. Second, TCF1 and LEF1 are required for Treg survival under competitive conditions. Thus, TCF1 and LEF1 play critical roles in Treg homeostatic maintenance and Tfr generation.

2019-09-05 | GSE117726 | GEO

proteomic profiling of small extracellular vesicles (EVs), released by chronic myeloid leukemia cells K562

Project description:Chronic and acute myeloid leukemia (CML/AML) evade immune surveillance and induce immunosuppression, largely by upregulating Foxp3+ regulatory T cells (Treg). However, mechanisms that drive Treg in myeloid leukemias are largely unknown. Here, we show that leukemic (CML- and AML-derived) extracellular vesicles (EVs) drive human Treg, by de novo induction of Treg and by upregulating suppressive phenotype and activity of Treg. Rab27a-mediated EVs secretion contributed to Treg expansion, activity, and leukemic engraftment in vivo in a mouse model of CML-like disease. Leukemic EVs downregulated mTOR-S6 and upregulated STAT5 signaling in T cells, to upregulate Foxp3 and Treg activity, as well as evoked significant transcriptomic changes in Treg. By using high resolution 23-color spectral flow cytometry we identified 2 distinct, highly suppressive subsets of Treg expanded by leukemic EVs, characterized by elevated expression of tumor Treg markers CCR8, CCR4, TIGIT, CD39, CD30, TNFR2 and IL21R. Finally, we identified 4 1BBL/TNFSF9 protein in leukemic EVs. Deficiency of 4-1BBL in leukemic cells and EVs resulted in lower expression of CD30, TNFR2 and LAG-3 on Treg and thus weaker effector phenotype. Collectively, our data pinpoint leukemic extracellular vesicles as a significant factor that drives regulatory T cells and immunosuppression in myeloid leukemias. Our results suggest that targeting of Rab27a and EVs secretion may be a viable therapeutic option in myeloid leukemias, whereas detection of 4 1BBL containing EVs could be used as an early biomarker of immunosuppression and leukemia development/relapse

2022-02-16 | PXD027240 | Pride

Effector regulatory T cell differentiation and immune homeostasis depend on the transcription factor Myb

Project description:FoxP3-expressing regulatory T (Treg) cells are essential to maintain immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly express genes critical for Treg cell function. Here we demonstrate that mice lacking the transcription factor Myb in Treg cells succumb to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and DNA binding analyses revealed that Myb directly regulates a large proportion of the effector Treg cell specific gene expression in mouse and human cells. This study identifies a critical role for Myb in the gene regulatory network controlling effector Treg cell differentiation and function.

2017-01-01 | GSE72494 | GEO

Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Project description:Project abstract: Foxp3+ T regulatory (Treg) cells have important functions in suppressing immune cell activation and establishing normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a co-activator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells disrupts immune homeostasis and results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate that Ndfip1 deficiency alters the metabolic signature of Treg cells. Metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Additional data suggest that Ndfip1 restricts Treg cell metabolic capacity and IL-4 production via distinct mechanisms. Thus, Ndfip1 preserves Treg lineage stability by preventing the expansion of highly proliferative and metabolically active cells that can cause immunopathology via secretion of IL-4.

2017-04-19 | PXD006251 | Pride

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