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CD8⁺ T lymphocyte is a main source of interferon-gamma production in Takayasu's arteritis.

ABSTRACT: Interferon-gamma (IFN-γ) is a cytokine involved in the pathogenesis of Takayasu's arteritis (TAK). However, the source of IFN-γ in TAK patients is not fully clear. We aimed to investigate the source of IFN-γ in TAK. 60 TAK patients and 35 health controls were enrolled. The lymphocyte subsets of peripheral blood were detected by flow cytometry, cytokines were detected by Bio-plex. The correlation among lymphocyte subsets, cytokines and disease activity indexes was analyzed by person correlation. The level of serum IFN-γ in TAK patients was significantly increased (P < 0.05). The percentage of CD3⁺IFN-γ⁺ cells in peripheral blood CD3⁺ cells was significantly higher in TAK patients than that of healthy control group (P = 0.002). A higher proportion of CD3⁺CD8⁺IFN-γ⁺ cells/CD3⁺IFN-γ⁺ cells (40.23 ± 11.98% vs 35.12 ± 11.51%, P = 0.049), and a significantly lower CD3⁺CD4⁺IFN-γ⁺/ CD3⁺CD8⁺IFN-γ⁺ ratio (1.34 ± 0.62% vs 1.80 ± 1.33%, P = 0.027) were showed in the TAK group than that of control group. The CD3⁺CD8⁺IFN-γ⁺/CD3⁺IFN-γ⁺ ratio was positively correlated with CD3⁺IFN-γ⁺cells/ CD3⁺cells ratio (r = 0.430, P = 0.001), serum IFN-γ level (r = 0.318, P = 0.040) and IL-17 level (r = 0.326, P = 0.031). It was negatively correlated with CD3⁺CD4⁺IFN-γ⁺/CD3⁺IFN-γ⁺ ratio (r = - 0.845, P < 0.001). IFN-γ secreted by CD3⁺CD8 ⁺ T cells is an important source of serum IFN-γ in TAK patients.

SUBMITTER: Ren YL

PROVIDER: S-EPMC8384861 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionMitogen-activated protein kinases (MAPKs) are involved in T cell-mediated liver damage. However, the inhibitory mechanism(s) that controls T cell-mediated liver damage remains unknown.ObjectivesWe investigated whether Spred2 (Sprouty-related, EVH1 domain-containing protein 2) that negatively regulates ERK-MAPK pathway has a biological impact on T cell-mediated liver damage by using a murine model.MethodsWe induced hepatotoxicity in genetically engineered mice by intravenously injecting Concanavalin A (Con A) and analyzed the mechanisms using serum chemistry, histology, ELISA, qRT-PCR, Western blotting and flow cytometry.ResultsSpred2-deficient mice (Spred2-/-) developed more sever liver damage than wild-type (WT) mice with increased interferon-γ (IFNγ) production. Hepatic ERK phosphorylation was enhanced in Spred2-/- mice, and pretreatment of Spred2-/- mice with the MAPK/ERK inhibitor U0126 markedly inhibited the liver damage and reduced IFNγ production. Neutralization of IFNγ abolished the damage with decreased hepatic Stat1 activation in Spred2-/- mice. IFNγ was mainly produced from CD4+ and CD8+ T cells, and their depletion decreased liver damage and IFNγ production. Transplantation of CD4+ and/or CD8+ T cells from Spred2-/- mice into RAG1-/- mice deficient in both T and B cells caused more severe liver damage than those from WT mice. Hepatic expression of T cell attractants, CXCL9 and CXCL10, was augmented in Spred2-/- mice as compared to WT mice. Conversely, liver damage, IFNγ production and the recruitment of CD4+ and CD8+ T cells in livers after Con A challenge were lower in Spred2 transgenic mice, and Spred2-overexpressing CD4+ and CD8+ T cells produced lower levels of IFNγ than WT cells upon stimulation with Con A in vitro.ConclusionWe demonstrated, for the first time, that Spred2 functions as an endogenous regulator of T cell IFNγ production and Spred2-mediated inhibition of ERK-MAPK pathway may be an effective remedy for T cell-dependent liver damage.

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CD8+ T lymphocyte is a main source of interferon-gamma production in Takayasu's arteritis.

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CD8⁺ T lymphocyte is a main source of interferon-gamma production in Takayasu's arteritis.