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TNF dependent induction of inhibitory pathways in CD4+ T cells in HIV and LCMV [TNF stimulation]

ABSTRACT: Chronic viral infections caused by HIV in humans or LCMV in mice are characterized by immunodeficiency and chronic inflammation. During chronification, T cells progressively lose effector functions, a process associated with immunoregulatory pathways and known as T-cell exhaustion. A link between ‘exhaustive’ T-cell reprogramming and chronic inflammation has not been established. Using a systems biology approach we demonstrate in HIV and LCMV infection that TNF, a prototypical mediator of chronic inflammation, functions upstream of major immunoregulatory pathways in T cells during chronic viral infection. In vivo blockade of TNFR-signaling interferes with the exhaustive T-cell program during chronic infection and reduces viral loads by several log. Continuous TNFR-signaling during disease progression towards chronic infection seems to be causative for T-cell exhaustion and an important link between immunodeficiency and chronic inflammation. TNF blockade might represent a novel therapeutic option during late stage infections caused by HIV and other virus causing chronic infections. TNF stimulation of CD4+ T cells to generate a CD4+ T-cell specific RNA-fingerprint

ORGANISM(S): Homo sapiens

PROVIDER: GSE52182 | GEO | 2016/03/07

SECONDARY ACCESSION(S): PRJNA227133

REPOSITORIES: GEO

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TNF dependent induction of inhibitory pathways in CD4+ T cells in HIV and LCMV [HIV-infected individuals]

Project description:Chronic viral infections caused by HIV in humans or LCMV in mice are characterized by immunodeficiency and chronic inflammation. During chronification, T cells progressively lose effector functions, a process associated with immunoregulatory pathways and known as T-cell exhaustion. A link between ‘exhaustive’ T-cell reprogramming and chronic inflammation has not been established. Using a systems biology approach we demonstrate in HIV and LCMV infection that TNF, a prototypical mediator of chronic inflammation, functions upstream of major immunoregulatory pathways in T cells during chronic viral infection. In vivo blockade of TNFR-signaling interferes with the exhaustive T-cell program during chronic infection and reduces viral loads by several log. Continuous TNFR-signaling during disease progression towards chronic infection seems to be causative for T-cell exhaustion and an important link between immunodeficiency and chronic inflammation. TNF blockade might represent a novel therapeutic option during late stage infections caused by HIV and other virus causing chronic infections.

2016-03-07 | GSE17606 | GEO

TNF dependent induction of inhibitory pathways in CD4+ T cells in HIV and LCMV [CD4+ T activation]

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TNF dependent induction of inhibitory pathways in CD4+ T cells in HIV and LCMV [chronic LCMV]

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TNF dependent induction of inhibitory pathways in CD4+ T cells in HIV and LCMV [acute LCMV]

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Role of NKG2a/c + CD8 + T cells in pathogenic versus non-pathogenic SIV infections

Project description:Some viruses have established an equilibrium with their host. African green monkeys (AGM) display persistent high viral replication in blood and intestine during Simian immunodeficiency virus (SIV) infection but resolve systemic inflammation after acute infection and lack intestinal immune or tissue damage during chronic infection. We show that NKG2 a/c + CD8 + T cells increase in blood and intestine of AGM in response to SIVagm infection in contrast to SIVmac infection in macaques, the latter modeling HIV infection. NKG2 a/c + CD8 + T cells were not expanded in lymph nodes and CXCR5 + NKG2 a/c + CD8 + T cell frequencies further decreased after SIV infection. Genome-wide transcriptome analysis of NKG2 a/c + CD8 + T cells from AGM revealed the expression of NK cell receptors, and of molecules with cytotoxic effector, gut homing, immunoregulatory and gut barrier function, including CD73. NKG2 a/c + CD8 + T cells correlated negatively with IL-23 in the intestine during SIVmac infection. The data suggest a potential regulatory role of NKG2 a/c + CD8 + T cells in intestinal inflammation during SIV/HIV infections.

2021-03-11 | E-MTAB-8664 | biostudies-arrayexpress

Distinct immune modulatory roles of regulatory T cells in gut versus joint inflammation in TNF driven spondyloarthritis [II]

Project description:Objectives: Gut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+ regulatory T (Treg) cells in a model of Crohn’s-like ileitis and concomitant arthritis. Methods: RNA-sequencing (RNA-seq) and flow cytometry were performed on inflamed gut and joint samples and tissue-derived Tregs from TNF∆ARE mice. In situ hybridization of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble(s) TNFR levels were measured in serum of mice and SpA patients and controls. Treg function was explored by in vitro co-cultures and in vivo by conditional Treg depletion. Results: Chronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 mRNA levels were noted in TNF∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in SpA patients with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆ARE mice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue restricted TNFSF receptor and p38MAPK gene expression. Conclusions: These data point to profound differences in immune-regulation between Crohn’s ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.

2023-05-22 | GSE232406 | GEO

Distinct immune modulatory roles of regulatory T cells in gut versus joint inflammation in TNF driven spondyloarthritis [I]

2023-05-22 | GSE232405 | GEO

Primary and secondary CD8 T cells during acute and chronic LCMV infection

Project description:Understanding the response of memory CD8 T cells to persistent antigen re-stimulation and the role of CD4 T cell help is critical to the design of successful vaccines for chronic diseases. However, studies comparing the protective abilities and qualities of memory and naïve cells have been mostly performed in acute infections, and little is known about their roles during chronic infections. Herein, we show that memory cells dominate over naïve cells and are protective when present in large enough numbers to quickly reduce infection. In contrast, when infection is not rapidly reduced, memory cells are quickly lost, unlike naïve cells. This loss of memory cells is due to (i) an early block in cell proliferation, (ii) selective regulation by the inhibitory receptor 2B4, and (iii) increased reliance on CD4 T cell help. These findings have important implications towards the design of T cell vaccines against chronic infections and tumors. 16 samples are analyzed: 3 replicates of secondary effector CD8 P14 T cells at day 8 post-acute lymphocytic choriomeningitis virus (LCMV) infection; 4 replicates of secondary effector CD8 P14 T cells at day 8 post-chronic LCMV infection; 4 replicates of primary effector CD8 P14 T cells at day 8 post-acute LCMV infection; and 5 replicates of primary effector CD8 P14 T cells at day 8 post-chronic LCMV infection.

2011-08-22 | E-GEOD-30962 | 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

Expression data from TNF-stimulated mouse glomeruli

Project description:The specific contribution of the two TNF-receptors Tnfr1 and Tnfr2 to TNF-induced inflammation in the glomerulus is unknown. In mice, TNF exposure induces glomerular expression of inflammatory mediators like adhesion molecules and chemokines in vivo, and glomerular accumulation of leukocytes. To examine Tnfr-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wild-type and Tnfr-deficient mice following TNF exposure in vitro. Glomeruli were isolated from male C57BL/6J wild-type and Tnfr-deficient mice applying a magnetic bead-based isolation technique. Isolated intact glomeruli were stimulated with TNF for 12 hours in vitro for subsequent RNA extraction and hybridization on Affymetrix microarrays.

2013-09-11 | E-GEOD-43928 | biostudies-arrayexpress

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