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ABSTRACT:
PROVIDER: PRJNA660590 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive CD4 T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4 T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells primarily suppress autoimmunity, pTreg cells are thought to enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms underlying their differentiation and function remain poorly understood. Here, we used genetic lineage tracing to unambiguously identify microbiota-induced pTreg cells and found that many of their distinct features were Foxp3-independent. Lineage-committed, microbiota-dependent pTreg-like cells persisted in the colon in the absence of Foxp3 protein. While Foxp3 was critical for the suppression of a Th17 cell program, colitis and rampant mastocytosis, pTreg cells suppressed colonic effector T cell expansion in a Foxp3-independent manner. Thus, Foxp3 and the tolerogenic signals that precede and promote its expression independently confer distinct facets of pTreg functionality.
2022-06-17 | GSE193780 | GEO
Project description:Understanding human regulatory T cells (Tregs) heterogeneity may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Treg (tTreg) and CD4+FOXP3+Helios- peripherally-induced Treg (pTreg), followed by comparison to CD4+FOXP3-Helios- T conventional (Tconv) cells. This analysis revealed that the coinhibitory receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was highly expressed on tTreg. In this study CD4 T cells were stained for the Treg-associated transcription factors FOXP3 and Helios, and subsequently FACS sorted to yield three populations: tTreg (CD4+FOXP3+Helios+), pTreg (CD4+FOXP3+Helios–) and the reference population Tconv (CD4+FOXP3–Helios–). A direct transcriptional profile was obtained from the recovered RNA from the populations defined as tTreg, pTreg, and Tconv.
2015-04-30 | E-GEOD-61834 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells expressing the X-linked lineage-defining transcription factor (TF) Foxp3 are essential for preventing fatal autoimmunity. During thymic differentiation, Foxp3 expression is induced in a subset of developing self-reactive thymocytes yielding thymic Treg (tTreg) cells, critical for enforcing tolerance to “self”. In the periphery, Foxp3 induction in mature naïve CD4 T cells activated under particular conditions results in extrathymic generation of Treg (pTreg) cells, thought to contribute to tolerance against commensal microbiota and dietary antigens. While Foxp3 is indispensable for tTreg cell differentiation and function, its role in pTreg cells has remained unknown. Here, we used complementary genetic approaches to characterize pTreg cells induced by microbial colonization and elucidate a role for Foxp3 in these cells. We found that a pTreg cell-specific gene expression program was installed in the gut-draining mesenteric lymph nodes (mLN) in a Foxp3-independent manner. In contrast to tTreg cells residing in the secondary lymphoid tissues, colonic microbiota-dependent pTreg cells did not depend on Foxp3 for their fitness or lineage commitment and were capable of preventing colonic effector T cell expansion in a Foxp3-independent manner. Rather, Foxp3 acted in a cell intrinsic manner to limit IL-17 production and was critical for the suppression of rampant intestinal mastocytosis. Thus, in contrast to tTreg cells, whose functionality is entirely Foxp3-dependent, Foxp3 expression plays a notably nuanced role in pTreg cells and acts to fine-tune the activity of IL-17 producing cells with Foxp3-independent regulatory functions.
2022-06-17 | GSE176293 | GEO
Project description:Regulatory T (Treg) cells expressing the lineage-defining transcription factor Foxp3 are essential for the maintenance of immune tolerance. Foxp3 expression can be induced in a subset of developing self-reactive thymocytes to yield thymic Treg (tTreg) cells, critical for tolerance against self-antigens. Alternatively, activation of mature naïve T cells under non-inflammatory conditions can drive the differentiation of peripherally-induced Treg (pTreg) cells, thought to contribute to tolerance against commensal microbes and dietary antigens. While Foxp3 is indispensable for tTreg cell development and function, its role in pTreg cells has remained unknown. Here, we used a genetic fate mapping approach to characterize polyclonal pTreg cells induced by microbial colonization. We found that expression of a pTreg cell-specific gene expression program was initiated in the mesenteric lymph node (mLN) in a Foxp3-independent manner. Moreover, in contrast to Treg cells in secondary lymphoid tissues, colonic microbiota-dependent pTreg cells did not depend on Foxp3 for their fitness or lineage commitment and were capable of suppressing colonic effector T cell expansion in a Foxp3-independent manner. Rather, Foxp3 was required in a cell-intrinsic manner to limit IL-17 production and to prevent the expansion of intestinal mast cells. Our results suggest that, extrathymic Foxp3 induction likely acts as a mechanism to fine-tune the activity of Th17-like cells with Foxp3-independent regulatory functions.
2021-12-31 | GSE176235 | GEO
Project description:Regulatory T (Treg) cells expressing the lineage-defining transcription factor Foxp3 are essential for the maintenance of immune tolerance. Foxp3 expression can be induced in a subset of developing self-reactive thymocytes to yield thymic Treg (tTreg) cells, critical for tolerance against self-antigens. Alternatively, activation of mature naïve T cells under non-inflammatory conditions can drive the differentiation of peripherally-induced Treg (pTreg) cells, thought to contribute to tolerance against commensal microbes and dietary antigens. While Foxp3 is indispensable for tTreg cell development and function, its role in pTreg cells has remained unknown. Here, we used a genetic fate mapping approach to characterize polyclonal pTreg cells induced by microbial colonization. We found that expression of a pTreg cell-specific gene expression program was initiated in the mesenteric lymph node (mLN) in a Foxp3-independent manner. Moreover, in contrast to Treg cells in secondary lymphoid tissues, colonic microbiota-dependent pTreg cells did not depend on Foxp3 for their fitness or lineage commitment and were capable of suppressing colonic effector T cell expansion in a Foxp3-independent manner. Rather, Foxp3 was required in a cell-intrinsic manner to limit IL-17 production and to prevent the expansion of intestinal mast cells. Our results suggest that, extrathymic Foxp3 induction likely acts as a mechanism to fine-tune the activity of Th17-like cells with Foxp3-independent regulatory functions.
2021-12-31 | GSE176236 | GEO
Project description:To investigate the molecular mechanisms of how CTSW regulates pTreg cells generation and function, we performed mRNA sequencing and found a set of genes regulated by Foxp3 was differentially expressed in CTSW-deficient compared to control pTreg cells
2023-07-17 | GSE225785 | GEO
Project description:Foxp3 is the master transcription factor for the regulatory T cells (Tregs). Alternative splicing of human Foxp3 results in the expression of two isoforms: the full-length and an exon 2-deleted protein. Here, AlphaFold2 predictions and in vitro experiments demonstrate that the N-terminal domain of Foxp3 inhibits DNA binding by moving toward the C-terminus and that this movement is mediated by exon 2. Consequently, we find Foxp3∆2-bearing tTregs in the peripheral lymphoid organ are less sensitive to TCR due to the enhanced binding of Foxp3∆2 to the Batf promoter and are unsusceptible to IL-2. In contrast, among RORγt+ pTregs in the large intestine, Foxp3∆2 pTregs express much more RORγt-related genes conferring a competitive advantage. Together, our results reveal that alternative splicing of exon 2 generates a constitutively active form of Foxp3, which plays a differential role in regulating tTregs and pTregs homeostasis.
2023-11-19 | GSE236356 | GEO
Project description:Understanding human regulatory T cells (Tregs) heterogeneity may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Treg (tTreg) and CD4+FOXP3+Helios- peripherally-induced Treg (pTreg), followed by comparison to CD4+FOXP3-Helios- T conventional (Tconv) cells. This analysis revealed that the coinhibitory receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was highly expressed on tTreg.
2015-04-30 | GSE61834 | GEO
Project description:We have performed a single cell sequencing assay by using DNBelab C high-throughput single-cell RNA-seq system to study intratumoral Treg cells. Treg cells promote tumorigenesis by suppressing immune responses against tumor. FOXP3 protein is the master controller of Treg function. In human, FOXP3 gene produces two isoforms by the alternative splicing of exon 2. However, mouse only produces full-length FOXP3. This study analyzed the gene expression profile of intracellular Treg cells from wild-type mice or Foxp3 humanized mice which produce both full-length and exon 2-skipped FOXP3 protein.
2026-06-03 | GSE306731 | GEO
Project description:Antigen-specific regulatory T cells (Tregs) in the gut are essential for maintaining immune tolerance, yet the contributions of different antigen sources and TCR identities to peripheral Treg (pTreg) differentiation remain poorly understood. In this study, we replaced endogenous TCRs in CD4⁺ Tconv cells (CD45.2⁺) with defined TCRs using an AAV-based system. Tconv cells expressing TCRs reactive to food (TF2.2, TF2.7, TF2.6), E. coli Nissle (TM3.5, TM2.3, TM1.2), or self antigens (TS2.3, TS2.1) were transferred into CD45.1⁺ hosts carrying the corresponding antigens. Ten days post-transfer, we performed single-cell RNA sequencing on donor-derived pTreg cells sorted from pooled mesenteric lymph nodes (mLNs), based on Foxp3-GFP expression. In parallel, we profiled TCR-edited transferred cells that did not convert to Foxp3⁺. As negative controls, we included non-edited and TCR-negative donor cells that had undergone the same in vitro culture and transfer process but did not receive differentiation-inducing signals. For comparison with endogenous T cell populations, we also included host-derived CD25hi Tregs as well as GFP⁺ and GFP⁻ cells from age-matched Foxp3-GFP mice.
2026-05-11 | GSE301231 | GEO