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Systemic inflammation drives rapid conversion of conventional CD4+ T cells to Treg in vivo

ABSTRACT: The immune system faces a task that approximates cognition in its complexity as it processes a multitude of intrinsic and extrinsic signals and integrates these into responses of the appropriate class, specificity, magnitude, and duration for a given threat, with the host’s life often depending on the outcome. CD4+ T lymphocytes occupy a unique role in the generation and regulation of immunity within this context and influence multiple innate and adaptive cell types. With respect to CD8+ cytotoxic T lymphocytes (CTL), CD4+ T cells function early in the response as ‘helpers’ (TH) to increase its magnitude and functionality, and later as regulatory cells (Treg) to restore homeostasis and avoid immune pathology. Using a Listeria monocytogenes (Lm) infection model, we probed whether the conditions of initial pathogen encounter could influence the generation of TH versus Treg. At low dose infection, CD4+ T cells ‘help’ CTLs via CD40-CD40L signaling, while high dose infection induces rapid polyclonal conversion to functional FoxP3+CD25+ Treg within 24 hours. These findings resolve long-standing questions regarding the requirement for TH and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Treg in vivo in response to acute inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE106554 | GEO | 2020/04/20

REPOSITORIES: GEO

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Systemic inflammation drives rapid conversion of conventional CD4+ T cells to Treg in vivo.

Project description:The immune system faces a task that approximates cognition in its complexity as it processes a multitude of intrinsic and extrinsic signals and integrates these into responses of the appropriate class, specificity, magnitude, and duration for a given threat, with the host’s life often depending on the outcome. CD4+ T lymphocytes occupy a unique role in the generation and regulation of immunity within this context and influence multiple innate and adaptive cell types. With respect to CD8+ cytotoxic T lymphocytes (CTL), CD4+ T cells function early in the response as ‘helpers’ (TH) to increase its magnitude and functionality, and later as regulatory cells (Treg) to restore homeostasis and avoid immune pathology. Using a Listeria monocytogenes (Lm) infection model, we probed whether the conditions of initial pathogen encounter could influence the generation of TH versus Treg. Infection induces rapid polyclonal conversion to functional FoxP3+CD25+ Treg within 24 hours. These findings resolve long-standing questions regarding the requirement for TH and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Treg in vivo in response to acute inflammation.

2021-03-27 | GSE169741 | GEO

Project Title: Proteome analysis of CD4+ T cell subsets

Project description:Functionally distinct CD4+ helper T (Th) cell subsets, such as Th1, Th2, Th17, and regulatory T cells (Treg), play a pivotal role in the host-defense against pathogen invasion and the pathogenesis of inflammatory disorders. In this project, DIA-MS-based proteome analysis was performed on naïve CD4+ T, Th0, Th1, Th2, Th17 and iTreg cells using Q Exactive HF-X (Thermo Fisher Scientific) to search for proteins that differ among the cell subsets.

2023-01-04 | PXD036065 | JPOST Repository

Human activated Treg cells and retrovirally engineered Th cells, transduced with GARP, FOXP3 or control GFP vector

Project description:Goals and objectives of this study: to identify genes of the Treg signature induced by consitutive expression of GARP or FOXP3 in antigen-specific Th cells with potential role for stabililization & maintenance of the regulatory program. Keywords: T-cell receptor stimulation, gene-regulation, comparative gene expression profiling, cell type comparison, human, regulatory T cells, FOXP3, GARP Human alloantigen-specific Treg cells (THU) and Th cells (CD4-39), established and described recently (Ocklenburg et al.. Lab Invest.2006; 86: 724-737), were sitmulated for 3 days with cognate antigen (EBV B cells) and IL2 as described (Ocklenburg et al.. Lab Invest.2006; 86: 724-737) and analyzed using human Affymetrix U133 2.0 in monoplicate. Th cells had been transduced with a retroviral vector containing human GARP (LRRC32) or FOXP3 and an IRES-driven GFP as marker or empty GFP control, sorted for GFP+, expanded as described recently (Ocklenburg et al.. Lab Invest.2006; 86: 724-737), and characterized functially, phenotypically, and genetically as described (WO/2007/113301). Abbreviations: Treg THU d3 = alloantigen-specific Treg cells; GFP d3 = GFP-transduced alloantigen-specific Th cells (CD4-39); FoxP3 d3 = FOXP-transduced alloantigen-specific Th cells (CD4-39); Garp d3 = GARP-transduced alloantigen-specific Th cells (CD4-39); all stimulated for 3 days (=d3) with EBV B cells and IL2.

2009-04-20 | E-GEOD-13234 | 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

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Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [scRNA-seq]

Project description:Inhibiting PD1:PDL1 signaling has transformed therapeutic immune restoration. CD4 T cells are critical to sustain immunity in chronic infections and cancer, yet little is known about how PD1/L1 modulates CD4 T helper (Th) responses or the ability to restore CD4 Th-mediated immunity by inhibiting PD1/L1 signaling. We demonstrate that PD1/L1 specifically suppresses CD4 Th1 cell amplification, prevents CD4 Th1 cytokine production, and abolishes CD4 CTL killing capacity during chronic infection. Inhibiting PDL1 during chronic infection rapidly restored these functions, while simultaneously enhancing Th1-like Treg amplification and activation, indicating a system-wide CD4-Th1 recalibration. Paradoxically, PDL1-blockade decreased TCR signaling, while re-directing intrinsically-suppressive type I interferon networks towards dominant IFNγ-mediated responses. Mechanistically, PDL1-blockade specifically targeted defined populations with pre-established, but actively-suppressed proliferative potential, with limited impact on minimally-cycling TCF1+ Tfh, despite high PD1 expression. Thus, CD4 T cells require unique differentiation and functional states to be targets of PDL1-directed suppression and therapeutic restoration.

2021-09-20 | GSE163343 | GEO

Dynamic CD4 T cell heterogeneity defines subset-specific suppression and PDL1-blockade driven functional restoration in chronic infection [Bulk-seq]

2021-09-20 | GSE163259 | GEO

Complex immune evasion strategies in classical Hodgkin lymphoma

Project description:The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Th and Treg cells presumably provide essential survival signals for HRS cells. Treg cells are also involved in rescuing HRS cells from anti-tumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only highly relevant for a characterization of the pathophysiology of cHL, but also clinically, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4+ T cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4+ Th and Treg cells isolated from cHL lymph nodes and reactive tonsils revealed that Treg cell signatures were enriched in CD4+ Th cells of cHL. Hence, HRS cells may induce a Treg differentiation in Th cells, which was supported by in vitro studies with Th cells and cHL cell lines. Furthermore, we found indication for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs BTLA-HVEM and CD200R-CD200 in promoting immune evasion. Taken together, this study reveals that the immune evasion strategies in cHL are even more complex and multifaceted than previously recognized.

2017-10-09 | GSE102693 | GEO

Transcription profiling of human Th cells expressing Foxp3 and UBD ectopically

Project description:Expression analysis revealed that UBD is a down-stream element of Foxp3 in human activated regulatory CD4+ T cells (Treg). Experiment Overall Design: Comparison of expression profiles measured in naturally occuring regulatory T-cells (Treg), Foxp3 and UBD transformed Th cells versus their controls with respect to the observed regulatory phenotype.

2008-06-13 | E-GEOD-4527 | biostudies-arrayexpress

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

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

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