Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and ...Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ2 cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells (the predominant subtype of γδ T cells in peripheral blood) were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4+ T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memoryVγ9Vδ2 T cells simultaneously secreted not only interferon (IFN)-γbut also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, 78 T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4+ T cells, thus sustaining CD4+ T-cell activation.展开更多
γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells a...γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδT cell, which may account for the dysfunction of Vδ2 γδT cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR+ γδ T cells and CD38+HLA-DR+ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.展开更多
γδ-T cells play an indispensable role in host defense against different viruses, including influenza A virus. However, whether these cells have cytotoxic activity against influenza virus-infected lung alveolar epith...γδ-T cells play an indispensable role in host defense against different viruses, including influenza A virus. However, whether these cells have cytotoxic activity against influenza virus-infected lung alveolar epithelial cells and subsequently contribute to virus clearance remains unknown. Using influenza virus-infected A549 cells, human lung alveolar epithelial cells, we investigated the cytotoxic activity of aminobisphosphonate pamidronate (PAM)-expanded human Vγ9Vδ2-T cells and their underlying mechanisms. We found that PAM could selectively activate and expand human Vγ9Vδ2-T cells. PAM-expanded human Vγ9Vδ2-T cells efficiently killed influenza virus-infected lung alveolar epithelial cells and inhibited virus replication. The cytotoxic activity of PAM-expanded Vγ9Vδ2-T cells was dependent on cell-to-cell contact and required NKG2D activation. Perforin-granzyme B, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-Fas ligand (FasL) pathways were involved in their cytotoxicity. Our study suggests that targeting γδ2-T cells by PAM can potentially offer an alternative option for the treatment of influenza virus.展开更多
The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not complet...The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.展开更多
Preterm and small-for-gestational-age (SGA) neonates are vulnerable groups that are susceptible to various microbial infections. Vγ9Vδ2-T cells are critical components of the host immune system and have been demon...Preterm and small-for-gestational-age (SGA) neonates are vulnerable groups that are susceptible to various microbial infections. Vγ9Vδ2-T cells are critical components of the host immune system and have been demonstrated to play an important role in the defense against viral infection in adults. However, the characteristics of Vγ9Vδ2-T cells in children, especially the preterm and SGA populations, are poorly understood. Here, we examined the frequency and antiviral function of Vγ9Vδ2-T cells in neonates, including preterm, SGA and full-term babies. When compared to adults, neonates had a significantly lower percentage of Vγ9Vδ2-T cells in the blood. Upon influenza virus stimulation, neonatalVγ9Vδ2-T cells, especially from preterm and SGA babies, showed markedly decreased and delayed antiviral cytokine responses than those of adults. In addition, the antiviral responses of neonatal Vγ9Vδ2-T cells were positively correlated with gestational age and birth weight. Finally, a weaker expansion ofVγ9Vδ2-T cells by isopentenyl pyrophosphate (IPP) was shown in neonates than the expansion in adults. Our data suggest that the depressed antiviral activity and decreased frequency of Vγ9Vδ2-T cells may likely account for the high susceptibility to microbial infection in neonates, particularly in preterm and SGA babies. Improving Vγ9Vδ2-T -cell function of neonates may provide a new way to defend against virus infection.展开更多
基金ACKNOWLEGEMENTS This work was supported by the grants from the following: National Natural Science Foundation of China (no. 30471593, 30872304 and 81072470), Shanghai Commission of Science and Technology (no. 10IC14 08500 and 10ZR1426100), Shanghai Leading Academic Discipline-Surgery (no. $30204- K01), Shanghai Municipal education Commission (no. 150207 and 09YZ102), Shanghai Institute of Immunology (no. 08-A04), Clinical Medicine Technology Development Foundation of Jiangsu University (no. ILY2010091) and Foundation of Shanghai Xuhui Central Hospital (no. 2011XHCH07).
文摘Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ2 cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells (the predominant subtype of γδ T cells in peripheral blood) were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4+ T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memoryVγ9Vδ2 T cells simultaneously secreted not only interferon (IFN)-γbut also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, 78 T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4+ T cells, thus sustaining CD4+ T-cell activation.
文摘γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδT cell, which may account for the dysfunction of Vδ2 γδT cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR+ γδ T cells and CD38+HLA-DR+ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.
基金This work was supported in part by the National Natural Science Foundation of China (No. 30973235), Science and Technology Project of the Sichuan Science and Technology Department (2010SZ0110), General Research Fund, Research Grants Council of Hung Kong (HKU 781211M) and the Area of Excellence Scheme of the University Grants Committee, Hung Kong SAR, China (AoE/M-12/06).
文摘γδ-T cells play an indispensable role in host defense against different viruses, including influenza A virus. However, whether these cells have cytotoxic activity against influenza virus-infected lung alveolar epithelial cells and subsequently contribute to virus clearance remains unknown. Using influenza virus-infected A549 cells, human lung alveolar epithelial cells, we investigated the cytotoxic activity of aminobisphosphonate pamidronate (PAM)-expanded human Vγ9Vδ2-T cells and their underlying mechanisms. We found that PAM could selectively activate and expand human Vγ9Vδ2-T cells. PAM-expanded human Vγ9Vδ2-T cells efficiently killed influenza virus-infected lung alveolar epithelial cells and inhibited virus replication. The cytotoxic activity of PAM-expanded Vγ9Vδ2-T cells was dependent on cell-to-cell contact and required NKG2D activation. Perforin-granzyme B, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-Fas ligand (FasL) pathways were involved in their cytotoxicity. Our study suggests that targeting γδ2-T cells by PAM can potentially offer an alternative option for the treatment of influenza virus.
基金This work was funded by INSERM,CNRS,the University Hospital of Bordeaux,and Toulouse III University.We acknowledge ImCheck for providing the 103.2 antibody and the 7.48 antibody.We are grateful to our healthcare professionals for their boundless efforts during the COVID-19 crisis.
文摘The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies.However,the molecular mechanism of their activation by phosphoantigens(PAgs)is not completely known.Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells,such as immune presenting cells or tumor cells.In this study,we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs,involving their TCR and the butyrophilins BTN3A1 and BTN2A1.This is the first time that these three molecules,concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells,have been shown to be involved together on the same and unique T cell during PAg activation.Moreover,the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed byγ9TCR,BTN3A1 and BTN2A1.The self-activation of Vγ9Vδ2 T cells,which leads to self-killing,can therefore participate in the failure ofγδT cell-based therapies with exogenous PAgs and should be taken into account.
基金ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation of China (No. 30973235 and 81170606), the Science and Technology project of the Sichuan Science and Technology Department (2010SZ0110), the General Research Fund from the Research Grants Council of Hong Kong (HKU 781211M) and the Area of Excellence Scheme of the University Grants Committee, Hong Kong SAR, China (AoE/M- 12/06).
文摘Preterm and small-for-gestational-age (SGA) neonates are vulnerable groups that are susceptible to various microbial infections. Vγ9Vδ2-T cells are critical components of the host immune system and have been demonstrated to play an important role in the defense against viral infection in adults. However, the characteristics of Vγ9Vδ2-T cells in children, especially the preterm and SGA populations, are poorly understood. Here, we examined the frequency and antiviral function of Vγ9Vδ2-T cells in neonates, including preterm, SGA and full-term babies. When compared to adults, neonates had a significantly lower percentage of Vγ9Vδ2-T cells in the blood. Upon influenza virus stimulation, neonatalVγ9Vδ2-T cells, especially from preterm and SGA babies, showed markedly decreased and delayed antiviral cytokine responses than those of adults. In addition, the antiviral responses of neonatal Vγ9Vδ2-T cells were positively correlated with gestational age and birth weight. Finally, a weaker expansion ofVγ9Vδ2-T cells by isopentenyl pyrophosphate (IPP) was shown in neonates than the expansion in adults. Our data suggest that the depressed antiviral activity and decreased frequency of Vγ9Vδ2-T cells may likely account for the high susceptibility to microbial infection in neonates, particularly in preterm and SGA babies. Improving Vγ9Vδ2-T -cell function of neonates may provide a new way to defend against virus infection.