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Type I interferon signaling attenuates Regulatory T cells function in LCMV infection

ABSTRACT: Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute and chronic infectious diseases remains unclear. We recently demonstrated that IFN- receptor (IFNAR) signaling promotes Treg function in autoimmunity. To dissect the functional role of IFNAR-signaling in Tregs during acute and chronic viral infection, we infected Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice with LCMV Armstrong and Clone-13. In both models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced expression of Treg associated activation antigens. The enhanced activated phenotype was also seen when we compared the transcriptomes of IFNARfl/flxFoxp3YFP-Cre and wild type (WT) Tregs by RNA-Seq on day 25-post Clone-13 infection. LCMV-specific CD8+ T cells from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral IFN and TNF in both acute and chronic LCMV. In the chronic model, the numbers of anti-viral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs than WT mice during chronic infection. Thus, type I IFN signaling in Tregs is context-dependent, resulting in enhanced suppressor function in some models of autoimmunity, but decreased suppressor function in acute and chronic viral infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE93909 | GEO | 2017/10/24

SECONDARY ACCESSION(S): PRJNA362815

REPOSITORIES: GEO

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Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment

Project description:Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute/chronic infectious diseases and in the tumor microenvironment remains unclear. We recently demonstrated that IFN-a/b receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here, we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic LCMV Clone-13 infection, and in a transplantable colon adenocarcinoma model. In both viral and tumor models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced Treg associated activation antigens. The enhanced activated phenotype was also seen when we compared the transcriptomes of IFNARfl/flxFoxp3YFP-Cre mice Tregs with the wild type (WT) Tregs by RNA-Seq on day 5 Armstrong and day 25-post Clone-13 infection. LCMV-specific CD8+ T cells and tumor infiltrating lymphocytes from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral and antitumor IFN-g and TNF-a. In the chronic infection model, the numbers of antiviral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs during chronic infection, and a higher tumor burden than the WT controls. Thus, type I IFN signaling in Tregs is context-dependent, resulting in enhanced suppressor function in some models of autoimmunity, but decreased suppressor function in acute/chronic viral infection and in the tumor microenvironment.

2017-10-24 | GSE104507 | GEO

Gene expression profiles of CD4+CD25+ regulatory T cells during acute and chronic viral infection

Project description:Regulatory T (Treg) cells act as terminators in the case of T cell immunity during the acute phase of viral infection. However, their roles in chronic viral infection are not completely understood. We compared the phenotype and function of Treg cells during acute and chronic viral infection using lymphocytic choriomeningitis virus-infected mouse models. Chronic infection, unlike acute infection, led to induction of Treg cells and upregulation of various inhibitory receptors. Treg cells isolated from chronically infected mice (chronic Treg cells) displayed greater suppressive capacity for inhibiting T cell proliferation and subsequent cytokine production than those from naM-CM-/ve (naive Treg cells) or acutely infected mice (acute Treg cells). These gene expression profiles provided evidence that chronic Treg cells display characteristics distinct from either naive or acute Treg cells. Mouse splenic CD4+CD25+ regulatory T cells were analyzed at 0 day and 16 day after acute or chronic viral infection with LCMV Arm or CL13, respectively.

2014-12-05 | E-GEOD-63876 | biostudies-arrayexpress

Changes in chromatin accessibility assocaiated with CD8 T cell responses to viral infections

Project description:The goal of this study was to identify the molecular programming using ATAC-seq of CD8 T cells responding to different viral infections. Mice were infected with either LCMV Armstrong to model an acute infection or LCMV Clone-13 to model a chronic infection. At various time points following infection, virus-specific CD8 T cells were purified and ATAC-seq performed. These data identify the changes in chromatin accessibility associated with acute infections and the establishment of functional memory versus those accessibility changes associated with chronic infection.

2017-01-31 | GSE83081 | GEO

Novel lymphocytic choriomeningitis virus strain sustains abundant exhausted progenitor CD8 T cells without systemic viremia

Project description:Lymphocytic choriomeningitis virus (LCMV) is the prototypic arenavirus and a natural mouse pathogen. LCMV Armstrong, an acutely resolved strain, and LCMV Clone 13, a mutant that establishes chronic infection, have provided contrasting infection models that continue to inform the fundamental biology of T cell differentiation, regulation of exhaustion, and response to checkpoint blockade. Here, we report the isolation and characterization of LCMV Minnesota (LCMV-MN), which was naturally transmitted to laboratory mice upon cohousing with pet shop mice and shares 80-95% amino acid homology with previously characterized LCMV strains. Infection of laboratory mice with purified LCMV-MN resulted in viral persistence that was intermediate between LCMV Armstrong and Clone 13, with widely disseminated viral replication and viremia that was controlled within 15-30 days, unless CD4 T cells were depleted prior to infection. LCMV-MN responding CD8+ T cells biased differentiation towards the recently described PD1+ CXCR5+ Tim-3lo stem-like CD8+ T cell population (also referred to as T exhausted progenitors, Tpex) that effectuates responses to PD-1 blockade checkpoint inhibition, a therapy that rejuvenates responses against chronic infections and cancer. This subset resembled previously characterized PD1+ TCF1+ stem-like CD8+ T cells by transcriptional, phenotypic, and functional assays, yet was atypically abundant. LCMV-MN may provide a tool to better understand the breadth of immune responses in different settings of chronic antigen stimulation as well as the ontogeny of T exhausted progenitors and the regulation of responsiveness to PD-1 blockade.

2022-08-22 | GSE207983 | GEO

Comparison of monocytic cells from naïve mice and day 14 LCMV Armstrong and day 14 LCMV Clone 13 infected mice

Project description:Infection with acute and chronic strains of LCMV (Armstrong (ARM) and Clone 13 (C13), respectively) leads to massive proliferation of monocytic cells contemporaneously with peak of the anti-viral CD8+ T cell response. These cells return to naïve levels following ARM infection. However, during C13 infection these cells are sustained at high levels and gain a T cell suppressive function at day 14 post infection. The mechanisms by which these cells are induced to proliferate and impair T cell function during chronic LCMV infection are largely unknown. To address this, we analyzed gene expression profiles using microarray analysis of purified splenic monocytic cells (CD11b+ Ly6Chi Gr-1low) from naïve mice, or day 14 LCMV ARM or LCMV C13 infected mice.

2013-02-25 | GSE43896 | GEO

Whole mouse genome analysis of LCMV-specific CD4 and CD8 T cells throughout acute and chronic LCMV infection.

Project description:CD4 and CD8 T cells display functional defects during chronic infection such as loss of certain cytokines. Recent studies have suggested that CD4 T cells may actually gain other functions, however. Here, we analyzed gene expression profiles from LCMV-specific CD4 and CD8 T cells throughout the response to either acute LCMV or chronic LCMV infection. This alllowed us to identify CD4-specific changes during chronic infection compared to acute infection but also revealed shared core regulators between CD4 and CD8 T cells. LCMV-specific CD4 and CD8 T cells were isolated 6, 8, 15 and 30 days post infection with LCMV Armstrong or LCMV clone 13. Naïve CD4 and CD8 T cells were also isolated from naïve mice as comparisons. Four replicates of each sample were hybridized. The only exception is LCMV-specific CD4 T cells isolated 6 days post infection with LCMV-Arm where only three replicates were hybridized.

2012-12-12 | E-GEOD-30431 | biostudies-arrayexpress

LCMV-Armstrong infection

Project description:LCMV-Armstrong infection

| PRJNA733467 | ENA

Gene expression profile analysis of mouse whole spleen following infection by lymphocytic choriomeningitis virus (LCMV), comparing LCMV-Armstrong and LCMV-Clone 13 expression patterns at 0, 5, 9, and 30 days

Project description:To identify mechanisms behind immunosuppression during virus infections, we infected mice with LCMV-Armstrong and LCMV-Clone 13 expression patterns. LCMV-Armstrong induces a T-cell reaction that resolves infection within 8-10 days, while LCMV-Clone13 generates a persisten infection through immunosuppression. We used microarray to uncover splenic gene expression patterns specific to each LCMV infection at 5, 9, and 30 days C57BL6 mice, 6-10 weeks old, were infected with LCMV-Armstrong and LCMV-Clone 13 or left uninfected (naïve). At days 5, 9, and 30 whole spleens were harvested for RNA extraction and hybridization on Affymetric microarray.

2013-02-15 | E-GEOD-44322 | biostudies-arrayexpress

Interferon gamma-induction of TH1-like regulatory T cells controls anti-viral responses

Project description:Regulatory T cells (Tregs) are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage during immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. We report that Tregs acquire an effector-like state, yet remain stable and functional, when exposed to IFNγ during chronic infection with lymphocytic choriomeningitis (LCMV) and Influenza A virus (IAV). Mechanistically, Treg-restricted-deletion of the IFNγ receptor 1 (IFNGR1), but not the IL12 receptor, prevented TH1-like polarization (decreased expression of T-bet, CXCR3 and IFNγ) and promoted TH2-like polarization (increased expression of GATA-3, CCR4 and IL4). TH1-like Tregs limited CD8+ T cell effector function, proliferation and memory formation during chronic and acute infection. These findings provide fundamental insights into how Tregs sense inflammatory cues from the environment (IFNγ) during viral infection to provide immune guidance to the effector T cell response, to prevent prolonged immunoinflammatory responses and shape the quality of the memory response.

2023-01-23 | GSE223210 | GEO

Hypoxia-inducible factors enhance CD8+ T cell effector responses to persistent antigen.

Project description:Cytolytic activity by CD8+ cytotoxic T lymphocytes (CTL) is a powerful tactic in the elimination of intracellular pathogens and tumor cells. The destructive capacity of CTL is progressively dampened during chronic infection - yet the environmental cues and molecular pathways controlling immune “exhaustion” remain unclear. We find CTL immunity is regulated by the central transcriptional response to hypoxia, mediated by the von-Hippel-Lindau/Hypoxia-Inducible-Factor (VHL/HIF) pathway. Deletion of VHL, the primary negative regulator of HIF, leads to lethal CTL-mediated immunopathology during chronic infection, and VHL-deficient CTL display enhanced control of persistent viral infection and neoplastic growth. We find HIF and oxygen influence expression of pivotal CTL transcription, effector and costimulatory-inhibitory molecules, which is relevant to strategies to promote viral and tumor clearance. To understand the role of the VHL/HIF pathway in regulating T cell responses to acute and persistant antigen in vivo, a mixture of ~10^4 WT and Vhl KO virus-specific CD8+ T cells (P14s) was transferred iv into uninfected WT host mice. After infection with either LCMV-Armstrong (acute viral infection) or LCMV-clone13 (persistent viral infection) we double-FACS isolated the responding P14 donor cells from pooled spleens from two sets of host mice to obtain duplicates for microarray for the four conditions, resulting in eight samples (2 WT Arm, 2 VHL KO Arm; 2 WT cl13, 2 VHL KO cl13) at 6 to 7 days post-infection. All conditions were sorted on KRLG1lo P14 cells. Note this was a mixed P14 transfer, so WT and KO cells were responding to infection in the same WT host mice to aid in normalizing effects such as antigen load and cytokine environment.

2013-09-29 | E-GEOD-50158 | biostudies-arrayexpress

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