Mechanisms of Treg cell dysfunction in activated mtDNANZB mice.
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ABSTRACT:
PROVIDER: PRJNA1181003 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the underlying mechanisms of Treg cell dysfunction in the mtDNANZB mice during activation, we compared the gene expression profiles of resting and activated Treg cells from mtDNAB6 and mtDNANZB mice.
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Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.
2009-09-15 | E-GEOD-16210 | biostudies-arrayexpress
Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Keywords: Normal vs Activated
2009-08-31 | GSE16210 | GEO
Project description:Although several markers have been associated with the characterization of regulatory T cells (Treg) and their function, no studies have investigated the dynamics of their phenotype during infection. Since the necessity of Treg to control immunopathology has been demonstrated, we used the chronic helminth infection model S. mansoni to address the impact on the Treg gene repertoire. Before gene expression profiling we first chose to study the localization and antigen-specific suppressive nature of classically defined Treg during infection. Presence of Foxp3+ cells were found especially in the periphery of granulomas and isolated CD4+CD25hiFoxp3+ Treg from infected mice blocked IFN-gamma and IL-10 cytokine secretion from infected CD4+CD25- effector T cells (Teff). Furthermore the gene expression patterns of Treg and Teff showed that in total 474 genes were significantly regulated during chronic schistosomiasis. Upon k-means clustering we identified genes exclusively regulated in all four populations including Foxp3, CD103, GITR, OX40 and CTLA-4: classical Treg markers. During infection however, several non-classical genes were up-regulated solely within the Treg population such as Slpi, Gzmb, Mt1, Fabp5, Nfil3, Socs2, Gpr177 and Klrg1. Using RT-PCR we confirmed aspects of the microarray data and in addition showed that the expression profile of Treg from S. mansoni-infected mice is simultaneously unique and comparative with Treg derived from other infections Regulatory T cells (Treg) or effector T cells (Teff) were FACS-sorted as CD4+CD25+ or CD4+CD25- from mesenteric lymph nodes (MLN) of naive mice or from mice infected with Schistosoma mansoni. Affymetrix MOE430A 2.0 genechips were used to identify genes differentially expressed in Treg or Teff under resting or infected conditions.
2010-04-12 | E-GEOD-17580 | biostudies-arrayexpress
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
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2023-02-09 | PXD037922 | Pride
Project description:Targeting histone/protein deacetylase (HDAC)-6, -9, or Sirtuin-1 (Sirt1) augments the suppressive functions of Foxp3+ T regulatory (Treg) cells, but it is unclear if this involves different mechanisms, such that combined inhibition would be beneficial. We compared the suppressive functions of Tregs from wild-type C57BL/6 mice or mice with global (HDAC6-/-, HDAC9-/-, dual HDAC6/9-/-) or conditional deletion (CD4-Cre or Foxp3-Cre and floxed Sirt1; GSE26425) alone, or after treatment with isoform-selective HDAC inhibitors (HDACi). We found the heat shock response was crucial in mediating the effects of HDAC6, but not Sirt1 inhibition. Furthermore, while HDAC6, HDAC9 and Sirt1 all deacetylate Foxp3, each has diverse effects on Foxp3 transcription, and loss of HDAC9 is associated with stabilization of Stat5 acetylation and its transcriptional activity. Targeting different HDAC can increase Treg function by multiple and additive mechanisms, indicating the therapeutic potential for combinations of HDACi in the management of autoimmunity and alloresponses post-transplant. RNA from three independent samples of magnetically separated CD4+CD25+ Treg of HDAC9-/- mice, compared to wild type (C57BL/6) control.
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Project description:Thymic-derived natural T regulatory cells (nTregs) are characterized by functional and phenotypic heterogeneity. Recently, a small fraction of peripheral Tregs have been shown to express Klrg1, but it remains unclear the extent Klrg1 defines a unique Treg subset. Here we show that Klrg1+ Tregs represent a terminally differentiated Treg subset derived from Klrg1- Tregs. This subset is a recent antigen-responsive and a highly activated short-lived Treg population that expresses enhanced levels of Treg suppressive molecules and that preferentially resides within mucosal tissues. The development of Klrg1+ Tregs also requires extensive IL-2R signaling. This activity represents a distinct function for IL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and other properties are analogous to terminally differentiated short-lived CD8+ T effector cells. Our findings suggest that an important pathway driving antigen-activated conventional T lymphocytes also operates for Tregs. Gene expression analysis was performed of this and other Treg subsets based on expression of CD62L, CD69, and Klrg1 to define the molecular properties of Klrg1+ Tregs and its relationship to other Treg subsets found in the peripheral immune tissues. Mice were euthanized, spleen cell preparations were made, and each Treg subset was isolated by FACS cell sorting. RNA was immediately prepared for processing.
2012-08-06 | E-GEOD-36527 | biostudies-arrayexpress
Project description:Primary immune regulatory disorders (PIRD) are a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad spectrum of clinical features and prior studies have documented a decreased frequency of Foxp3+ regulatory T (Treg) cells and an increased frequency of Th17 cells is some patients. However, the precise mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation and CD4+ Th1 cell skewing. Surprisingly, Treg cell numbers, phenotype, and function remained largely intact, however mice had a selective deficiency in the generation of iTreg cells. In parallel, we performed single-cell RNA-sequencing on T cells from patients with STAT3 GOF syndrome. We demonstrate only minor changes in the Treg cell transcriptional signature and an expanded, effector CD8+ T cell population. Together, these finding suggest Treg cells are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.
2022-10-14 | GSE207934 | GEO