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Foxp3-dependent and -independent functions of peripherally-induced regulatory T cells: scRNA-seq

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE176293 | GEO | 2022/06/17

REPOSITORIES: GEO

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Foxp3 Dependent and Independent Functions of Peripherally Induced Regulatory T Cells: colonic scRNA+TCR-seq

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

Foxp3-dependent and -independent functions of peripherally-induced Treg cells [09748]

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

Foxp3-dependent and -independent functions of peripherally-induced Treg cells [08075]

2021-12-31 | GSE176235 | GEO

Immune Gene Expression Profile of Conventional and Regulatory T cells

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

Immune Gene Expression Profile of Conventional and Regulatory T cells

2015-04-30 | GSE61834 | GEO

mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis

Project description:Regulatory T (Treg) cells derived from the thymus (tTreg) and periphery (pTreg) play central and distinct roles in immunosuppression, but mechanisms governing the generation and activation of Treg subsets in vivo remain uncertain. Here, we report that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tTreg and pTreg cells. Further, mTOR signaling is crucial for programming activated Treg cell effector function to protect immune tolerance and tissue homeostasis. Treg-specific deletion of mTOR drives spontaneous TH2 responses and altered barrier tissue homeostasis, associated with reductions in both thymic derived effector Treg (eTreg) and pTreg cells. Mechanistically, mTOR acts downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, disruption of mitochondrial metabolism severely impairs Treg cell suppressive function and their homeostasis in tissues. Collectively, our results demonstrate that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis

2019-09-12 | GSE104130 | GEO

Helios expression defines two distinct populations of Foxp3+ Treg cells

Project description:The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs of both mouse and man. We previously demonstrated that Treg induced in peripheral sites (pTreg) from Foxp3- T conventional (Tconv) cells were Helios- and proposed that Helios is a marker of thymic derived Treg (tTreg). To compare the two Treg subpopulations, we generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype and had a higher suppressive capacity in vitro. Both populations expressed a highly demethylated TSDR and both subsets were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios- Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios- Treg when transferred to lymphopenic mice. Gene expression profiling of the two populations demonstrated a large number of differentially expressed genes and that Helios- Treg subpopulation expressed certain genes normally expressed in CD4+Foxp3- T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios- Treg. Thus, Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct, consistent with thymic and peripheral sites of origin, respectively. Because of their superior suppressive activity and enhanced stability Foxp3+Helios+ Treg represent the optimal Treg population for cellular immunotherapy.

2019-01-24 | GSE117989 | GEO

The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes

Project description:Intestinal Foxp3+ regulatory T cell (Treg) subsets are crucial players in tolerance to microbiota-derived and food-borne antigens, and compelling evidence suggests that the intestinal microbiota modulates their generation, functional specialization, and maintenance. Selected bacterial species and microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), have been reported to promote Treg homeostasis in the intestinal lamina propria. Furthermore, gut-draining mesenteric lymph nodes (mLNs) are particularly efficient sites for the generation of peripherally induced Tregs (pTregs). Despite this knowledge, the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated. Here, using an adoptive transfer-based pTreg induction system, we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs. Even mice housed under germ-free (GF) conditions displayed equivalent pTreg induction within mLNs. Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape. Overall, our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.

2021-03-24 | GSE149851 | GEO

Gene expression profile of regulatory T cell (Treg) subsets from CD28-deficient mouse

Project description:A comparative analysis of gene expression of CD4+ EGFP+ Nrp1+ (tTreg, thymus-derived Treg), CD4+ EGFP+ Nrp1- (pTreg, peripherally-derived Treg) and CD4+ EGFP- (Tconv, conventional T cell) in CD28-/- Foxp3EGFP and Foxp3EGFP mice.

2017-06-29 | GSE92376 | GEO

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

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