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Pathogenic function of bystander-activated memory-like CD4⁺ T cells in autoimmune encephalomyelitis.

ABSTRACT: T cells generate antigen-specific immune responses to their cognate antigen as a hallmark of adaptive immunity. Despite the importance of antigen-specific T cells, here we show that antigen non-related, bystander memory-like CD4⁺ T cells also significantly contribute to autoimmune pathogenesis. Transcriptome analysis demonstrates that interleukin (IL)-1?- and IL-23-prime T cells that express pathogenic T_?17 signature genes such as ROR?t, CCR6, and granulocyte macrophage colony-stimulating factor (GM-CSF). Importantly, when co-transferred with myelin-specific 2D2 TCR-transgenic naive T cells, unrelated OT-II TCR-transgenic memory-like T_H17 cells infiltrate the spinal cord and produce IL-17A, interferon (IFN)-?, and GM-CSF, increasing the susceptibility of the recipients to experimental autoimmune encephalomyelitis in an IL-1 receptor-dependent manner. In humans, IL-1R1^high memory CD4⁺ T cells are major producers of IL-17A and IFN-? in response to IL-1? and IL-23. Collectively, our findings reveal the innate-like pathogenic function of antigen non-related memory CD4⁺ T cells, which contributes to the development of autoimmune diseases.

SUBMITTER: Lee HG

PROVIDER: S-EPMC6372661 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Pathogenic function of bystander-activated memory-like CD4+ T cells in autoimmune encephalomyelitis.

Lee Hong-Gyun HG Lee Jae-Ung JU Kim Do-Hyun DH Lim Sangho S Kang Insoo I Choi Je-Min JM

Nature communications 20190212 1

T cells generate antigen-specific immune responses to their cognate antigen as a hallmark of adaptive immunity. Despite the importance of antigen-specific T cells, here we show that antigen non-related, bystander memory-like CD4+ T cells also significantly contribute to autoimmune pathogenesis. Transcriptome analysis demonstrates that interleukin (IL)-1β- and IL-23-prime T cells that express pathogenic TΗ17 signature genes such as RORγt, CCR6, and granulocyte macrophage col ...[more]

PMID: 30755603

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Project description:BackgroundMicrovesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood.MethodsCD4+ T cells isolated from peripheral blood of healthy human donors were stimulated using anti-CD3/anti-CD28-coated beads. Proteomic profiling of microvesicles was performed using linear discriminant analysis (LDA) from activated T cells (MV.Act) and nonactivated T cells (MV.NAct). In addition, data processing analysis was performed using MaxQUANT workflow. Differentially expressed proteins found in MV.Act or MV.NAct samples with identification frequency = 100%, which were selected by both LDA (p < .01) and MaxQUANT (p < .01) workflows, were defined as "high-confidence" differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed.ResultsT cells released large amounts of microvesicles upon stimulation. Proteomic profiling of microvesicles using LDA identified 2279 proteins (n = 2110 and n = 851 proteins in MV.Act and MV.NAct, respectively). Protein-protein interaction network models reconstructed from both differentially expressed proteins (n = 594; LDA p ≤ .01) and "high-confidence" differentially expressed proteins (n = 98; p ≤ .01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organisation and TNFα-induced apoptosis. For instance, MV.Act were highly enriched with IFN-γ, a key proinflammatory pathway related to effector CD4+ T cells. Endothelial cell incubation with MV.Act induced superoxide generation, apoptosis, endothelial wound healing impairment and endothelial monolayer barrier disruption.ConclusionsT cell receptor-mediated activation of CD4+ T cells stimulates the release of microvesicles enriched with proteins involved in immune responses, inflammation and apoptosis. T cell-derived microvesicles alter microvascular endothelial function and barrier permeability, potentially promoting tissue inflammation.

Dataset Information

Pathogenic function of bystander-activated memory-like CD4⁺ T cells in autoimmune encephalomyelitis.

Publications

Pathogenic function of bystander-activated memory-like CD4<sup>+</sup> T cells in autoimmune encephalomyelitis.

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