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In order to promote the innovative application of Sanjiao theory and Yingwei theory， this paper tries to apply the ''Sanjiao-Yingwei'' Qi transformation theory to the treatment of tumor diseases， integrating it with T cell exhaustion mechanism to elaborate on its scientific connotation and using network pharmacology and bioinformatics to elucidate the correlation between the anti-tumor mechanism of ''Sanjiao-Yingwei'' Qi transformation and T cell exhaustion. The ''Sanjiao-Yingwei'' Qi transformation function is closely related to the immunometabolic ability of the human body， and the ''Sanjiao-Yingwei'' Qi transformation system constitutes the immunometabolic exchange system within and outside the cellular environment. Cancer toxicity is generated by the fuzzy Sanjiao Qi， and the long-term fuzzy Sanjiao Qi is the primary factor leading to T cell exhaustion， which is related to the long-term activation of T cell receptors by the high tumor antigen load in the tumor microenvironment. Qi transformation malfunction of the Sanjiao produces phlegm and collects stasis， which contributes to T cell exhaustion and is correlated with nutrient deprivation， lipid accumulation， and high lactate levels in the immunosuppressed tumor microenvironment， as well as with the release of transforming growth factor-β and upregulated expression of programmed death receptor-1 by tumor-associated fibroblasts and platelets in the tumor microenvironment. Ying and Wei damage due to Sanjiao Qi transformation malfunction is similar to the abnormal manifestations such as progressive loss of exhausted T cell effector function and disturbance of cellular energy metabolism. Guizhi decoction， Shengming decoction， and Wendan decoction can correct T cell exhaustion and exert anti-tumor effects through multi-target and multi-pathways by regulating ''Sanjiao-Yingwei'' Qi transformation， and hypoxia inducible factor-1α （HIF-1α） may be one of the main pathways to correct T cell exhaustion. It was found that HIF-1α may be one of the important prognostic indicators in common tumors by bioinformatics. The use of the ''Sanjiao-Yingwei'' Qi transformation method may play an important part in improving the prognosis of tumor patients in clinical practice.
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Objective: T lymphocyte exhaustion is an important component of immune dysfunction. Therefore, exploring peripheral blood-exhausted T lymphocyte features in patients with hepatitis B virus-related acute-on-chronic liver failure may provide potential therapeutic target molecules for ACLF immune dysfunction. Methods: Six cases with HBV-ACLF and three healthy controls were selected for T-cell heterogeneity detection using the single-cell RNA sequencing method. In addition, exhausted T lymphocyte subpopulations were screened to analyze their gene expression features, and their developmental trajectories quasi-timing. An independent sample t-test was used to compare the samples between the two groups. Results: Peripheral blood T lymphocytes in HBV-ACLF patients had different differentiation trajectories with different features distinct into eight subpopulations. Among them, the CD4(+)TIGIT(+) subsets (P = 0.007) and CD8(+)LAG3(+) (P = 0.010) subsets with highly exhausted genes were significantly higher than those in healthy controls. Quasi-time analysis showed that CD4(+)TIGIT(+) and CD8(+)LAG3(+) subsets appeared in the late stage of T lymphocyte differentiation, suggesting the transition of T lymphocyte from naïve-effector-exhausted during ACLF pathogenesis. Conclusion: There is heterogeneity in peripheral blood T lymphocyte differentiation in patients with HBV-ACLF, and the number of exhausted T cells featured by CD4(+)TIGIT(+)T cell and CD8(+)LAG3(+) T cell subsets increases significantly, suggesting that T lymphocyte immune exhaustion is involved in the immune dysfunction of HBV-ACLF, thereby identifying potential effective target molecules for improving ACLF patients' immune function.
Subject(s)
Humans , Hepatitis B virus , Acute-On-Chronic Liver Failure/pathology , Hepatitis B, Chronic , T-Lymphocyte Subsets/pathology , Receptors, ImmunologicABSTRACT
Objective:To investigate the potential molecular mechanisms of liver cancer cell-derived secretory autophagosomes, extracellular vesicles expressing LC3B (LC3B + EVs), in promoting the exhaustion of CD8 + T cells. Methods:The proportions of LC3B + EVs and PD-1 + CD8 + T cells in peripheral blood and ascites of liver cancer patients were measured by flow cytometry. Spearman correlation test was used to analyze the correlation between the proportions of LC3B + EVs and PD-1 + CD8 + T cells. Peripheral blood mononuclear cells (PBMCs) from healthy donors were treated with LC3B + EVs or heat shock protein 90α (HSP90α) blocking antibody-pretreated LC3B + EVs for 72 h in the presence of αCD3/CD28 antibodies and IL-2 in vitro. The proportions of PD-1 + CD8 + T and IFN-γ + CD8 + T cells and the concentrations of IL-2, TNF-α and IFN-γ in the supernatants were all detected by flow cytometry. Results:The proportions of LC3B + EVs and HSP90α + LC3B + EVs in plasma and ascites from liver cancer patients were significantly higher than those in healthy control group and non-cancerous ascites group. The level of plasma LC3B + EVs, especially HSP90α + LC3B + EVs, was significantly correlated with the percentage of exhausted PD-1 + CD8 + T cells. In addition, LC3B + EVs from human liver cancer cells up-regulated the percentage of exhausted CD8 + T cells in vitro. However, LC3B + EVs pretreated with HSP90α blocking antibody could significantly inhibit LC3B + EVs-induced CD8 + T cell exhaustion. Conclusions:Liver cancer cell-derived LC3B + EVs could effectively induce CD8 + T cell exhaustion mainly through the membrane-bound HSP90α.
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OBJECTIVES: To investigate the expression levels of surface markers of activation (CD38 and HLA-DR), inhibition (PD-1, TIGIT and CD57) and co-stimulation (CD28 and CD127) on CD4+ T cells of children/adolescents with vertical HIV infection (HI patients) and HIV-uninfected (HU) controls vaccinated with the meningococcal C conjugate vaccine (MCC). METHODS: HI patients (n=12), aged 8-17 years, were immunized with two MCC injections, while HU controls (n=9), aged 5.3-10.7 years, received a single MCC dose (as per national recommendation at the time of this study, a single MCC vaccine dose should be given for healthy children and youth aged 1-18 years). The HI patients were categorized according to the combined antiretroviral therapy (cART) treatment. Blood samples were obtained before vaccination, after priming, and after the administration of a booster dose of vaccine to determine the serum bactericidal antibody (SBA) titers and the expression levels of surface markers on CD4+ T cells by flow cytometry. The levels of serum cytokines, IL-4 and CXCL-13 were also measured using Luminex kits. RESULTS: The co-expression of the TIGIT-HLA-DR-CD38 molecules increased in the CD4+ T cells of HI patients/no-cART who also showed a lower frequency of CD127+CD28+ CD4+ T cells than HI patients/cART and HU group subjects. There were significant negative correlations between the frequency of exhausted CD4+ T cells and the SBA response. IL-4 levels were higher in HI patients/cART and positively correlated with SBA titers but negatively associated with the expression of exhaustion markers. Moreover, the CXCL-13 levels were positively correlated with the exhausted CD4+ T cells. CONCLUSION: The results of our study suggest that the co-expression of exhaustion markers and/or loss of co-stimulatory molecules influence the SBA response in HI patients.
Subject(s)
Humans , Child , Adolescent , HIV Infections , Meningococcal Vaccines , CD4-Positive T-Lymphocytes , Antibody FormationABSTRACT
Objective:To explore the expression and clinical significance of immunosuppressive receptor T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) on the peripheral blood mononuclear cells (PBMC) in silicosis patients with Mycobacterium tuberculosis infection. Methods:August 2018, a total of 78 patients with silicosis (all were quarry workers in Sanmen County, Zhejiang Province) were enrolled and divided into silicosis combined with active pulmonary tuberculosis group (APTB group), silicosis combined with latent tuberculosis infection group (LTBI group), and simple silicosis with non-tuberculosis infection group (non-TB group). Flow cytometry was used to analyze the expressions of TIGIT, programmed death-1 (PD-1) and transcription factor T-bet on PBMC from patients. Mann-Whitney U test and Pearson correlations analysis were used for statistical analysis. Results:Among the 78 patients, eight were in the APTB group, 24 in the LTBI group, and 46 in the non-TB group. The expressions of PD-1 and TIGIT on CD8 + T cells in the APTB group (29.45%(16.78%) and 65.40%(12.12%), respectively) were significantly higher than those in the LTBI group (17.40%(11.17%) and 48.30%(28.75%), respectively; U=23.500 and 43.500, respectively, P=0.000 8 and 0.020 5, respectively) and non-TB group (15.95%(12.46%) and 45.30%(19.75%), respectively; U=64.000 and 69.000, respectively, P=0.002 3 and 0.003 8, respectively), and the differences were all statistically significant. The expression of TIGIT was positively correlated with PD-1 on CD8 + T cells in silicosis patients ( r=0.434 3, P<0.01). The proportion of PD-1 + TIGIT + CD8 + T cells in the APTB group (19.90%(22.67%)) was significantly higher than those in the non-TB group (11.55%(11.29%), U=76.500, P=0.007 1) and LTBI group (11.55%(10.53%), U=41.000, P=0.015 4), while the proportion of PD-1 -TIGIT -CD8 + T cells in the APTB group (30.60%(12.90%)) was significantly lower than non-TB group (48.90%(18.98%), U=58.000, P=0.001 3) and LTBI group (47.20%(24.59%), U=41.000, P=0.015 4). The differences were all statistically significant. The expression of T-bet on the peripheral blood CD8 + T cells in the APTB group (29.45%(16.78%)) was higher than that in the non-TB group (15.95%(12.46%)) and the LTBI group (17.40%(11.17%)), and the differences were both statistically significant ( U=46.500 and 46.000, respectively, P=0.000 3 and 0.028 3, respectively). The expression of T-bet on CD8 + T cells was positively correlated with TIGIT on CD8 + T cells ( r=0.456 7, P<0.01). The expression of T-bet on PD-1 + TIGIT + CD8 + T cells in the APTB group (65.40%(12.12%)) was higher than those in the LTBI group (48.30%(28.75%), U=23.500, P=0.000 8) and non-TB group (45.30%(19.75%), U=65.000, P=0.002 6), and the differences were both statistically significant. Conclusion:The immunosuppressive receptor PD-1 and TIGIT are highly expressed on CD8 + T cells in silicosis patients with active pulmonary tuberculosis, which indicates CD8 + T cells exhaustion in these population, while the highly co-expression of T-bet suggests the exhausted subsets may have reversed potentiality.
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Acute viral infection or vaccination generates highly functional memory CD8 T cells following the Ag resolution. In contrast, persistent antigenic stimulation in chronic viral infection and cancer leads to a state of T-cell dysfunction termed T-cell exhaustion. We and other have recently identified a novel subset of exhausted CD8 T cells that act as stem cells for maintaining virus-specific CD8 T cells in a mouse model of chronic lymphocytic choriomeningitis virus infection. This stem cell-like CD8 T-cell subset has been also observed in both mouse and human tumor models. Most importantly, in both chronic viral infection and tumor models, the proliferative burst of Ag-specific CD8 T cells driven by PD-1-directed immunotherapy comes exclusively from this stem cell-like CD8 T-cell subset. Therefore, a better understanding of the mechanisms how CD8 T-cell subsets are regulated during chronic viral infection and cancer is required to improve the current immunotherapies that restore the function of exhausted CD8 T cells. In this review, we discuss the differentiation of virus-specific CD8 T cells during chronic viral infection, the characteristics and function of CD8 T-cell subsets, and the therapeutic intervention of PD-1-directed immunotherapy in cancer.
Subject(s)
Animals , Humans , Mice , Immunotherapy , Lymphocytic choriomeningitis virus , Memory , Stem Cells , T-Lymphocyte Subsets , T-Lymphocytes , VaccinationABSTRACT
Objective:To evaluate effects of Bushen Jianpi Recipe ( BSJP) on restoring of T cell exhaustion induced by persistent tuberculosis antigens in mice.Methods:The C57BL/6 mice were primed with BCG(5×106 CFU)and boosted with 20μg of Mycobacterium bovis BCG Purified Protein Derivative ( PPD ) once a week and lasted for 16 times to induce T cell exhaustion that happened in late stage of tuberculosis .BSJP was used to treat the mice with immune exhaustion for 3 weeks.Flow Cytometry was used to detect the numbers of CD 4+and CD8+T cells and PD-1 expression.ELISA was used to detect IL-2 and IFN-γsecretion.Bacteria load in lung tissue following BCG challeng was used to detect the protective capability of mice models .Results: Compared with the transient antigen stimulation group,the persistent antigen stimulation group had lower level of IFN-γand IL-2 secretions(P<0.01).The numbers of CD4+and CD8+T cells decreased and the level of inhibitory receptor PD-1 got higher(P<0.01).The protective efficacy against BCG challenging decreased ( P<0.01 ) .After treatment with BSJP , the production of cytokines IFN-γand IL-2 increased ( P<0.01 );the numbers of CD4+and CD8+T cells increased and PD-1 expression level on CD4+T cells decreased(P<0.01);the protective efficacy against BCG challenge increased (P<0.01).The results showed that BSJP can reduce the PD-1 expression,improve the IL-2 and IFN-γsecretion,and increase the protection against BCG challenge .Conclusion:Bushen Jianpi Recipe can restore T cell exhaustion induced by persistent tuberculosis antigen stimulation in mice , which gives a hope to overcome T cell exhaustion in tuberculosis with Chinese herbal in clinic.