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

ABSTRACT: To determine the effects of excess IL-18 and perforin deficiency on CD8 T cell clonality toegther and separately under homeostatic conditions. These data support that together perforin deficiency and excess IL-18 promote hyperexpansion of CD8 T cell clones.

ORGANISM(S): Mus musculus

PROVIDER: GSE226124 | GEO | 2023/09/28

REPOSITORIES: GEO

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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

Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation

Project description:Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation

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Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-28 | GSE226126 | GEO

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

Project description:Complementary HLH Susceptibility Factors Converge on CD8 T-cell Hyperactivation [TCR-seq]

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IL-6R identifies early differentiated human effector memory CD8+ T cells that potently expand and produce IL-2 and IL-13

Project description:We found a unique subset of effector memory (EM) CD8+ T cells that expressed high levels of IL-6 receptor in human peripheral blood. These cells which also expressed high levels of IL-7Ra (referred to as IL-6R high IL-7Rahigh cells) had the a distinct gene expression profile and cellular characteristics compared to other EM CD8+ T cells. IL-6R high IL-7Ra high cells were early differentiated EM CD8+ T cells with decreased expression of T-bet, KLRG1, perforin and granzyme B. These cells had increased cell proliferation likely secondary to enhanced IL-2 production and high affinity IL-2R expression. IL-6R high IL-7Ra high EM CD8+ T cells exclusively produced high levels of IL-2, IL-5, IL-9 and IL-13 although IFN-r was produced by this cell subset and other EM CD8+ T cells. Of interest, IL-6R high IL-7Ra high EM CD8+ T cells expanded in the peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and asthma where CD8+ T cells, IL-13 and IFN-r are suggested to be involved in the pathogenesis. Being the early-differentiated EM CD8+ T cells with a potent capacity to proliferate, survive and generate multiple cytokines, IL-6R high IL-7Ra high EM CD8+ T cells may serve as a primary reservoir for effector CD8+ T cells which potently expand and produce cytokines upon immune stimulation. Duplicate experiments were performed for each condition. In each condition, we independently prepared total RNA using the RNeasy mini kit (Qiagen) and assessed RNA integrity using Bioanalyzer 2100 (Agilent)- RINs were close to 10 for all samples. RNA was then amplified and hybridized to the Illumina HumanHT-12 v4.0 BeadChip, according to Illumina standard protocols.

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Interleukin-18 and cytotoxic impairment are independent and synergistic causes virus-induced hyperinflammation in mice

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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

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CD8 T cells induce perforin-dependent pathology in Leishmania braziliensis infection

Project description:The mechanisms that mediate immunopathologic responses in infectious diseases are often less well understood than how the pathogens are controlled. Here, we have investigated what causes increased pathology following infection with the protozoan parasite, Leishmania braziliensis. We focused on CD8 T cells since their presence in leishmanial lesions has been correlated with increased disease. By adoptively transferring CD8 T cells to L. braziliensis infected RAG mice, we found that unregulated CD8 T cells promote severe pathology at the infection site, as well as the development of metastatic lesions in other skin sites. In mice with severe pathology, we visualized CD8 T cells degranulating and lysing L. braziliensis infected cells, and in parallel studies with L. braziliensis patients we confirmed that CD8 T cells within lesions exhibit a cytolytic phenotype. We found that perforin deficient CD8 T cells failed to induce disease, indicating that the increased disease induced by CD8 T cells was due perforin-dependent cytotoxicity. In contrast, although we found that CD8 T cells made both IFN-γ and IL-17, neither of these cytokines is required for the development of pathology. Thus, we show for the first time that immunopathology in leishmaniasis can be mediated by cytolytic CD8 T cells. Twelve skin biopsy samples were analyzed, including 2 normal skin biopsies obtained from patients in N. America, and 10 skin biosies obtained from Leishmania brazilensis infected patients presenting at the Corte de Pedra Health Post in Corte de Pedra, Bahia, Brazil

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