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CD4⁺ T cells aggravate hemorrhagic brain injury.

ABSTRACT: Leukocyte infiltration accelerates brain injury following intracerebral hemorrhage (ICH). Yet, the involvement of T lymphocytes in this process has not been fully elucidated. Here, we report that CD4⁺ T cells accumulate in the perihematomal regions in the brains of patients with ICH and ICH mouse models. T cells activation in the ICH brain is concurrent with the course of perihematomal edema (PHE) development, and depletion of CD4⁺ T cells reduced PHE volumes and improved neurological deficits in ICH mice. Single-cell transcriptomic analysis revealed that brain-infiltrating T cells exhibited enhanced proinflammatory and proapoptotic signatures. Consequently, CD4⁺ T cells disrupt the blood-brain barrier integrity and promote PHE progression through interleukin-17 release; furthermore, the TRAIL-expressing CD4⁺ T cells engage DR5 to trigger endothelial death. Recognition of T cell contribution to ICH-induced neural injury is instrumental for designing immunomodulatory therapies for this dreadful disease.

SUBMITTER: Shi SX

PROVIDER: S-EPMC10246900 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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CD4+ T cells aggravate hemorrhagic brain injury.

Shi Samuel X SX Xiu Yuwen Y Li Yan Y Yuan Meng M Shi Kaibin K Liu Qiang Q Wang Xiaoying X Jin Wei-Na WN

Science advances 20230607 23

Leukocyte infiltration accelerates brain injury following intracerebral hemorrhage (ICH). Yet, the involvement of T lymphocytes in this process has not been fully elucidated. Here, we report that CD4+ T cells accumulate in the perihematomal regions in the brains of patients with ICH and ICH mouse models. T cells activation in the ICH brain is concurrent with the course of perihematomal edema (PHE) development, and depletion of CD4+ T cells reduced PHE volumes and improved n ...[more]

PMID: 37285421

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Project description:BackgroundAccumulating evidence supports the involvement of adaptive immunity in the development of radiation-induced brain injury (RIBI). Our previous work has emphasized the cytotoxic function of CD8+ T cells in RIBI. In this study, we aimed to investigate the presence and potential roles of cytotoxic CD4+ T cells (CD4+ CTLs) in RIBI to gain a more comprehensive understanding of adaptive immunity in this context.Main textUtilizing single-cell RNA sequencing (scRNA-seq), we analyzed 3934 CD4+ T cells from the brain lesions of four RIBI patients and identified six subclusters within this population. A notable subset, the cytotoxic CD4+ T cells (CD4+ CTLs), was marked with high expression of cytotoxicity-related genes (NKG7, GZMH, GNLY, FGFBP2, and GZMB) and several chemokine and chemokine receptors (CCL5, CX3CR1, and CCL4L2). Through in-depth pseudotime analysis, which simulates the development of CD4+ T cells, we observed that the CD4+ CTLs exhibited signatures of terminal differentiation. Their functions were enriched in protein serine/threonine kinase activity, GTPase regulator activity, phosphoprotein phosphatase activity, and cysteine-type endopeptidase activity involved in the apoptotic signaling pathway. Correspondingly, mice subjected to gamma knife irradiation on the brain showed a time-dependent infiltration of CD4+ T cells, an increase of MHCII+ cells, and the existence of CD4+ CTLs in lesions, along with an elevation of apoptotic-related proteins. Finally, and most crucially, single-cell T-cell receptor sequencing (scTCR-seq) analysis at the patient level determined a large clonal expansion of CD4+ CTLs in lesion tissues of RIBI. Transcriptional factor-encoding genes TBX21, RORB, and EOMES showed positive correlations with the cytotoxic functions of CD4+ T cells, suggesting their potential to distinguish RIBI-related CD4+ CTLs from other subsets.ConclusionThe present study enriches the understanding of the transcriptional landscape of adaptive immune cells in RIBI patients. It provides the first description of a clonally expanded CD4+ CTL subset in RIBI lesions, which may illuminate new mechanisms in the development of RIBI and offer potential biomarkers or therapeutic targets for the disease.

Project description:The influenza A (H1N1) pdm09 virus remains a critical global health concern and causes high levels of morbidity and mortality. Severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the major outcomes among severely infected patients. Our previous study found that interleukin (IL)-17A production by humans or mice infected with influenza A (H1N1) pdm09 substantially contributes to ALI and subsequent morbidity and mortality. However, the cell types responsible for IL-17A production during the early stage of severe influenza A (H1N1) pdm09 infection remained unknown. In this study, a mouse model of severe influenza A (H1N1) pdm09 infection was established. Our results show that, in the lungs of infected mice, the percentage of γδT cells, but not the percentages of CD4+Th and CD8+Tc cells, gradually increased and peaked at 3 days post-infection (dpi). Further analysis revealed that the Vγ4+γδT subset, but not the Vγ1+γδT subset, was significantly increased among the γδT cells. At 3 dpi, the virus induced significant increases in IL-17A in the bronchoalveolar lavage fluid (BALF) and serum. IL-17A was predominantly secreted by γδT cells (especially the Vγ4+γδT subset), but not CD4+Th and CD8+Tc cells at the early stage of infection, and IL-1β and/or IL-23 were sufficient to induce IL-17A production by γδT cells. In addition to secreting IL-17A, γδT cells secreted interferon (IFN)-γ and expressed both an activation-associated molecule, natural killer group 2, member D (NKG2D), and an apoptosis-associated molecule, FasL. Depletion of γδT cells or the Vγ4+γδT subset significantly rescued the virus-induced weight loss and improved the survival rate by decreasing IL-17A secretion and reducing immunopathological injury. This study demonstrated that, by secreting IL-17A, lung Vγ4+γδT cells, at least, in part mediated influenza A (H1N1) pdm09-induced immunopathological injury. This mechanism might serve as a promising new target for the prevention and treatment of ALI induced by influenza A (H1N1) pdm09.

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CD4⁺ T cells aggravate hemorrhagic brain injury.

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CD4<sup>+</sup> T cells aggravate hemorrhagic brain injury.

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