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Multimodal induction of hyperinflammation by IL-18 includes virus-specific NK immunodeficiency [NKILC1_RNAseq]

ABSTRACT: Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors and often an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (Il18tg), showed NK-cytopenia and baseline CTL activation resembling MAS-susceptible patients. NK transcriptomes indicated transcription/division with few changes in canonical NK programs. Infection of Il18tg mice with lymphocytic-choriomeningitis virus resulted in HLH/MAS but intact viral control. Early after NK-dependent mousepox infection, Il18tg NKs failed to appropriately activate but their CTLs became hyperactivated, and mousepox control remained intact. However, mousepox-infected Il18tg mice then developed hepatosplenic necrosis and other signs of HLH/MAS; and their poor viral control paralleled their failed expansion of mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18tg mice restored their virus-specific CTL response and rescued survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.

ORGANISM(S): Mus musculus

PROVIDER: GSE306508 | GEO | 2026/08/25

REPOSITORIES: GEO

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Multimodal induction of hyperinflammation by IL-18 includes virus-specific NK immunodeficiency [NKstim_RNAseq]

Project description:Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors and often an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (Il18tg), showed NK-cytopenia and baseline CTL activation resembling MAS-susceptible patients. NK transcriptomes indicated transcription/division with few changes in canonical NK programs. Infection of Il18tg mice with lymphocytic-choriomeningitis virus resulted in HLH/MAS but intact viral control. Early after NK-dependent mousepox infection, Il18tg NKs failed to appropriately activate but their CTLs became hyperactivated, and mousepox control remained intact. However, mousepox-infected Il18tg mice then developed hepatosplenic necrosis and other signs of HLH/MAS; and their poor viral control paralleled their failed expansion of mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18tg mice restored their virus-specific CTL response and rescued survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.

2026-08-25 | GSE306511 | GEO

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Project description:To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with Lymphocytic Choriomeningitis Virus (LCMV, Armstrong). LCMV infection is self-limited in wild-type (WT) mice, but Prf1-/- mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1-/- mice, albeit with minimal mortality. We use RNA-sequencing to identify differences in the transcriptome of GP33 - specific CD8 T cells from these mice in comparison to a wild type mouse under the same conditions. We saw expression of Ifng was elevated about 4-fold in both Prf1-/- and Il18tg mice. Genes specifically upregulated in Il18tg CD8 T-cells included Csf2, Il1rl1, and Il12rb2. We also saw differences between Prf1-/- and WT/Il18tg CD8 T-cells that included Klrg1 and transcripts associated with CD8 T-cell exhaustion, including the inhibitory receptors Lag3, Havcr2, and Tigit, and the transcription factors Tox and Prdm1. These data support that IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation, and support the rationale for an IL-18-driven subclass of hyperinflammation.

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Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation [bulk RNA-seq]

Project description:To determine the effects of excess IL-18 and perforin deficiency on CD8 T cells toegther and separately under homeostatic conditions. Mice harboring both excess IL-18 and perforin deficiency (DS) have increased activated (CD44+) CD8 t cells as well as a special CD44low/- CD62L- (DN) population of CD8 T cells. DS mice have CD8 T cells that have specifically upregulated inhibitory receptors Lag3, Havcr2, and Tigit, and the transcription factors Tox and Prdm1. Mice harboring excess IL-18 and partial perforin deficiency (DS-HET) as well as mice with only excess IL-18 (Il18tg) also have these signatures but only in the DN CD8 T cell population. These data support that IL-18 as a potent, independent, and modifiable driver of life-threatening innate nd adaptive hyperinflammation, and support the rationale for an IL-18-driven subclass of hyperinflammation.

2023-09-28 | GSE226125 | GEO

Effect of IL-12+IL-18 or anti-NK1.1 stimulation on splenic NK cells [mNK_Activation_RNA-seq]

Project description:We stimulated freshly enriched splenic NK cells with either IL-12+IL-18 (1ng/ml each) or plate-bound anti-NK1.1. NKs from several C57Bl/6 mice were pooled. We then performed gene expression profiling analysis using data obtained from RNA-seq at two time points: 3 or 6 hours.

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Project description:Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTL, and that deletion or depletion of Dicer in mouse or human activated CD8+ T cells causes upregulation of perforin, granzyme and effector cytokines. Genome-wide analysis of miRNA changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of a miRNA network that controls perforin, eomesodermin (Eomes) and IL-2Ra expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation and antigenic stimulation. Overall our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation. Comparison of control and Dicer knock-out CTLs differentiated in vitro; Comparison of wild type CTLs differentiated in vitro with or without inflammatory stimuli; Comparison of effector and memory precursor CTLs isolated from mice infected with LCMV-Armstrong

2013-12-02 | E-GEOD-51393 | biostudies-arrayexpress

Reprogramming of CTLs into natural killer-like cells in celiac disease

Project description:Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon g–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases. Keywords: NKG2C; LAK; CTL; NK receptor; IEL; Mucosal Immunity; Celiac Disease

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Gene expression profiles of human CD8+ T cells: IL-12 and IFN-a polarized in vitro stimulated and ex vivo sorted CCR7hi and CXCR3hi populations

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2011-09-29 | E-GEOD-27337 | biostudies-arrayexpress

The alarmin interleukin-33 drives protective antiviral CD8+ T cell responses

Project description:Pathogen-associated molecular patterns decisively influence antiviral immune responses, whereas the contribution of endogenous signals of tissue damage, also known as “damage-associated molecular patterns” or “alarmins”, remains ill-defined. We show that interleukin-33 (IL-33), an alarmin released from necrotic cells, is necessary for potent CD8+ T cell (CTL) responses to replicating, prototypic RNA and DNA viruses in mice. IL-33 signaled through its receptor on activated CTLs, enhanced clonal expansion in a MyD88-dependent, CTL-intrinsic fashion, determined polyfunctional effector cell differentiation and was necessary for virus control. Moreover, recombinant IL-33 augmented vaccine-induced CTL responses. Radio-resistant cells of the splenic T cell zone produced IL-33, and efficient CTL responses required IL-33 from radio-resistant cells but not from hematopoietic cells. Thus, alarmin release by radio-resistant cells orchestrates protective antiviral CTL responses. 2 groups (wt vs. ST-/- P14 cells), 3 replicates per group.

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