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Self-reactivity controls functional diversity of naive CD8⁺ T cells by co-opting tonic type I interferon.

ABSTRACT: The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise function and underlying mechanisms are unclear. Here, we demonstrate that naive CD8⁺ T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon, resulting in three distinct subsets, CD5^loLy6C^-, CD5^hiLy6C^-, and CD5^hiLy6C⁺ cells. CD5^hiLy6C⁺ cells differ from CD5^loLy6C^- and CD5^hiLy6C^- cells in terms of gene expression profiles and functional properties. Moreover, CD5^hiLy6C⁺ cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such features of CD5^hiLy6C⁺ cells are imprinted in a steady-state and type I interferon dependence is observed even for monoclonal CD8⁺ T cell populations. These findings demonstrate that self-reactivity controls the functional diversity of naive CD8⁺ T cells by co-opting tonic type I interferon signaling.

SUBMITTER: Ju YJ

PROVIDER: S-EPMC8523551 | 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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Self-reactivity controls functional diversity of naive CD8+ T cells by co-opting tonic type I interferon.

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Self-reactivity controls functional diversity of naive CD8⁺ T cells by co-opting tonic type I interferon.