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Human Th17 cells engage gasdermin E pores to release IL-1alpha upon NLRP3 inflammasome activation

ABSTRACT: Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here, we found that human T cells expressed gasdermin E (GSDME), a membrane pore-forming molecule that has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunneled release of the innate danger signal IL-1. This property was restricted to a subset of human Th17 cells with antigen specificity for C. albicans and was regulated by a T-cell-intrinsic NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T-cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL1 form. This equipped human Th17 cells with a so far overlooked effector function that contributes to the clearance of C. albicans. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This finding diversifies the functional repertoire and mechanistic equipment of T cells and thus suggests new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in anti-fungal host defense.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214292 | GEO | 2022/10/24

REPOSITORIES: GEO

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Human Th17 cells engage gasdermin E pores to release IL-1a upon NLRP3 inflammasome activation [Array]

Project description:Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here, we found that human T cells expressed gasdermin E (GSDME), a membrane pore-forming molecule that has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunneled release of the innate danger signal IL-1a. This property was restricted to a subset of human Th17 cells with antigen specificity for C. albicans and was regulated by a T-cell-intrinsic NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T-cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL1a form. This equipped human Th17 cells with a so far overlooked effector function that contributes to the clearance of C. albicans. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This finding diversifies the functional repertoire and mechanistic equipment of T cells and thus suggests new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in anti-fungal host defense.

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Human Th17 cells engage gasdermin E pores to release IL-1a upon NLRP3 inflammasome activation [RNA-seq]

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Project description:Adaptive immune responses are tailored to the invading microbial antigen and tissue microenvironment, resulting in diverse context-specific inflammatory signatures. There is emerging evidence that innate immune responses coopt adaptive properties such as memory. Whether T cells harness innate immune signaling pathways to diversify their repertoire of effector functions remains unknown. Here we show that human T cells can express gasdermin E (GSDME), a membrane pore forming molecule, which has recently been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In T cells, GSDME expression was, in contrast, associated with durable viability and was repurposed for the tunnelled release of the calpain-matured innate danger signal IL-1a. This property was restricted to a subset of human Th17 cells and regulated by the NLRP3 inflammasome and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage following T cell receptor stimulation. Autocrine IL-1a signaling enforced a pro-inflammatory Th17 cell fate through continuous IL-10 suppression and showed an association of this T cell subset with the autoinflammatory Schnitzler syndrome. Our results propose GSDME pore formation in T cells as a mechanism of unconventional cytokine release through harnessing of innate signaling platforms in response to adaptive stimuli. This diversifies the functional repertoire and mechanistic equipment of T cells and thus provides new therapeutic strategies for targeting the proinflammatory identity of human Th17 cells in various diseases.

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2022-05-20 | PXD030879 | Pride

STIM1-mediated gene expression in non-pathogenic and pathogenic CD4+ Th17 cells

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Project description:Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 release. However, certain stimuli and cell types release IL-1 cytokines through GSDMD pores in cells that remain viable, a process termed hyperactivation. How these distinct cell fate choices are regulated downstream of GSDMD pore formation is unknown. Here, we demonstrate that the Card19 locus promotes lysis downstream of caspase activation. Despite being largely protected from cell death, CARD19-deficient macrophages had no defect in caspase activation, IL-1 secretion, or GSDMD cleavage. CARD19, a mitochondrial protein, was not responsible for the observed phenotypes, nor was the recently identified pore forming protein NINJ1 which regulates terminal pore formation during multiple forms of cell death. Furthermore, previously identified cell death phenotypes attributed to Sterile alpha and heat Armadillo motif-containing protein (SARM) were revealed to be caused by a passenger mutation. Importantly, Card19-/ mice had increased susceptibility to Yersinia infection, including increased mortality, higher bacterial burdens and pronounced splenomegaly. These findings implicate the Card19 locus as a factor that couples caspase processing and GSDMD cleavage to cell death, providing insight into how the checkpoint between hyperactivation and cell death is regulated.

2021-03-21 | GSE168489 | GEO

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Project description:Alcohol-associated liver disease is accompanied by changes in the intestinal mycobiome. How fungal dysbiosis contributes to liver disease is not clear. T-helper (Th17) cells mediate immune responses against fungi, but the interleukin 17 (IL17) pathway has been associated with pathogenesis of alcohol-associated liver disease. Here, we demonstrate that Candida albicans (C. albicans)-specific Th17 cells are increased in the circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration to mice results in migration of C. albicans-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin reduced intestinal fungal overgrowth, decreased C. albicans-specific Th17 cells in the liver, and reduced features of ethanol-induced liver disease in mice. Transgenic mice that express a T-cell receptor (TCR) reactive to Candida antigens develop more severe ethanol-induced liver disease than transgene-negative littermates; disease severity was reduced by administration of an antibody against IL17 to the TCR transgenic mice. Adoptive transfer of C. albicans-reactive Th17 cells exacerbated ethanol-induced liver disease in wild-type mice. IL17 receptor A (IL17ra) signaling in Kupffer cells was required for the effects of C. albicans-reactive Th17 cells. Our findings indicate that ethanol increases C. albicans-reactive Th17 cells, which contribute to alcohol-associated liver disease.

2023-02-16 | GSE215930 | GEO

Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease [bulk TCR-seq]

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Comparison of gene expression profiles in naïve WT and Asc-null bone marrow derived dendritic cells

Project description:The adaptor protein ASC contributes to innate immunity through the assembly of caspase-1-activating inflammasome complexes. We demonstrate that ASC plays an inflammasome-independent cell-intrinsic role in adaptive immune cells. Asc-/- mice displayed defective antigen presentation by dendritic cells and lymphocyte migration due to impaired Rac-mediated actin polymerization. Genome-wide analysis showed that ASC, but not Nlrp3 or caspase-1, controls mRNA stability and expression of DOCK2, a guanine nucleotide exchange factor that mediates Rac-dependent signaling in immune cells. DOCK2-deficient dendritic cells showed similar defective antigen uptake as Asc-/- cells. Ectopic expression of DOCK2 in ASC-deficient cells restored Rac-mediated actin polymerization, antigen uptake and chemotaxis. Thus, ASC shapes adaptive immunity independently of inflammasomes by modulating DOCK2-dependent Rac activation and F-actin polymerization in dendritic cells and lymphocytes. Three replicates of naïve WT and three replicates of Asc-/- bone marrow derived dendritic cells were analyzed on the Affymetrix HT MG-430 PM plate array.

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