TCRαβ+NK1.1-CD4-CD8- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

Tian, Dan; Pan, Yuhualei; Zhao, Yingxin; Wang, Huan; Tian, Yue; Yang, Lu; Shi, Wei; Zhang, Chengjie; Zhu, Yanbing; Zhang, Yongbo; Wang, Songlin; Zhang, Dong

doi:10.7150/thno.80307

Cited by 11 publications

(4 citation statements)

References 45 publications

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“…Previous findings by our group demonstrated that a higher CCR5 was expressed in DNT [ 19 ]. To investigate how transferred DNT migrate into skin tissue, we performed transcriptome sequencing on the skin from control and IMQ-treated mice.…”

Section: Resultsmentioning

confidence: 91%

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Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells

Wei,

Sun,

Yang

et al. 2024

J Transl Med

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Background Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. Methods We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. Results DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5−/− DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. Conclusions DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

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Section: Resultsmentioning

confidence: 91%

“…DNT highly express CCR5, which is critical for DNT migration and function [ 19 ]. In our study, we also observed significantly increased CCL3/4 (CCR5 ligands) expression in the inflamed skin tissue of mice with psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells

Wei,

Sun,

Yang

et al. 2024

J Transl Med

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“…Ischemic stroke, comprising lacunar infarction, cardioembolic, and large artery atherosclerosis subtypes, represents a significant medical challenge [ 28 ]. T lymphocytes play a pivotal role in the pathophysiology of ischemic stroke, regulating the immune response and inflammatory processes in the body [ 52 ]. A comprehensive investigation into the dynamic changes of T lymphocytes following ischemic stroke revealed an increase in peripheral T lymphocyte numbers post-event [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring clinical indicator variations in stroke patients with multiple risk factors: focus on hypertension and inflammatory reactions

Guo,

Tian,

et al. 2024

Eur J Med Res

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Background Stroke stands as the second leading cause of death worldwide. Currently, extensive research has been conducted on stroke risk factors. However, when stroke patients contend with multiple risk factors, the impact on clinical indicators remains uncertain. Objectives This study seeks to investigate potential significant variations among distinct ranges of clinical indicators in instances where stroke patients experience multiple risk factors and various ischemic stroke subtypes. Material and methods The research encompassed 440 stroke patients admitted to the First People's Hospital of Wenling City, Zhejiang Province, China. These patients were classified based on the type and quantity of risk factors and subtypes of ischemic stroke they presented. The χ2 test was employed to assess the relationship between the risk of comorbid diseases and clinical indicators in stroke patients. Results The results of our study have underscored a significant correlation between various comorbid risk factors in stroke patients and the patients' age (P < 0.010). Furthermore, we observed noteworthy disparities in the plasma levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and INF-γ between patients devoid of risk factors and those presenting with comorbid risk factors associated with stroke. Significant differences in INF-γ were observed between the two subtypes of ischemic stroke, namely lacunar infarction and cardioembolic stroke. Conclusion Age is correlated with an elevated risk of stroke. Individuals exhibiting multiple stroke risk factors and diverse ischemic stroke subtypes commonly present with abnormal lipid levels and imbalances in Th1/Th2 cytokines. These factors significantly contribute to the onset and progression of stroke. Furthermore, inflammatory responses, particularly those induced by atherosclerosis, play a pivotal role in the genesis of stroke and exert a substantial influence on its prognosis.

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“…CCL25 in thymus chemoattracted DCs [36]. CD3 + NK1.1 − TCRβ + CD4 − CD8 − double-negative T (DNT) cells enhance Treg cell recruitment through CCL5 in ischemic stroke lesions [37]. Transendothelial DCs chemoattracted by endothelial ligand, CX3CL1, might help the thymus actively acquire blood-borne antigens to induce and maintain central tolerance [38].…”

Section: Discussionmentioning

confidence: 99%

Cancer Cachexia-related Monocytic MDSCs Impair T-cell Negative Selection and Predict Immune-related Adverse Events

Li,

Wei,

Huang

et al. 2024

Preprint

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Background Cancer cachexia is prevalent in multiple cancers and is associated with chemotherapy toxicity. However, data on the relationship between immune-related adverse events (irAEs) and cachexia are limited. Methods A murine model of orthotopic hepatocellular carcinoma (HCC) with cachexia was constructed to determine the effect of T-cell infiltration in multiple tumor-free organs on irAEs occurrence. Single-cell sequencing of thymic stromal cells was conducted. Patients with advanced cancers receiving anti-PD-1/L1 antibody treatment were followed up to investigate the relationship between cachexia and irAEs. Results Inflammatory cells infiltrated multiple tumor-free organs in cachexic HCC but not in non-cachexic mice. Immunofluorescence revealed that these infiltrating cells included CD4+ and CD8+ T-cells. Morphological assessment and hematoxylin-eosin staining confirmed thymus atrophy in cachexic HCC mice. Single-cell sequencing of thymic stromal cells showed fewer medullary thymic epithelial cells (mTECs) II and III in the thymus of cachexic mice than in those of non-cachexic mice. Aire downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs. T cells from cachexic HCC mice induced inflammation and T cell infiltration in multiple organs of tumor-free mice in an organ-specific manner. After administration of anti-mouse PD-1 antibody, the incidence of inflammation in multiple organs was much higher in cachexic HCC mice as well as tumor free mice transferred with T cells from cachexic HCC mice. Thymic monocytic myeloid-derived suppressor cells (M-MDSCs) enriched in cachexic HCC mice, evidenced by flow cytometer and immunofluorescence analyses. M-MDSCs infiltrated the thymus in cachexic mice with cancer. Cachexia-related M-MDSCs induced mTEC from tumor-free mice apoptosis through nitric oxide production in vitro. M-MDSCs transfer induced infiltration of inflammatory cells in multiple organs and thymus involution of tumor free mice without decreasing their weights. Sixty-four patients with advanced cancer receiving anti-PD-1/L1 antibody treatment were included in this study. Patients with irAEs displayed higher levels of circulating M-MDSCs than those without irAEs. Moreover, patients with cachexia (BMI < 20 kg/m2 or weight loss ≥ 5% over the past 6 months) had higher M-MDSC levels. Patients with high M-MDSC levels and low BMI or weight loss ≥ 5% experienced more irAEs (HR 2.333, 95% CI 1.231–4.423). Conclusions M-MDSCs induced mTEC apoptosis through nitric oxide production in cachexic mice with cancer, impairing T-cell negative selection and leading to autoimmune T-cell infiltration in tumor-free organs. Cancer cachexia-related M-MDSCs are potential predictive biomarkers of irAEs in patients with advanced cancer.

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TCRαβ⁺NK1.1^-CD4^-CD8^- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

Cited by 11 publications

References 45 publications

Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells

Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells

Exploring clinical indicator variations in stroke patients with multiple risk factors: focus on hypertension and inflammatory reactions

Cancer Cachexia-related Monocytic MDSCs Impair T-cell Negative Selection and Predict Immune-related Adverse Events

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