The Characteristics of Natural Killer Cells and T Cells Vary With the Natural History of Chronic Hepatitis B in Children

Background and Aims: The immune status of children with chronic hepatitis B (CHB) in different phases is still unclear. The aim of this study was to investigate the phenotype and cytokine-producing ability of natural killer (NK) and T cells and to better understand the immune characteristics of children with different phases of CHB.Methods: Treatment-naive children with CHB were divided into groups with different clinical phases of CHB. Fresh peripheral blood drawn from hepatitis B virus (HBV)-infected and healthy children was processed to perform flow cytometric analysis.Results: A total of 112 treatment-naive children with CHB and 16 comparable healthy controls were included in this study. The expression of HLA-DR on NK cells and CD38 on T cells were upregulated, especially in the IA phase, in children with CHB compared with healthy controls. The ability of circulating NK cells instead of CD8+ T cells to produce IFN-γ in children with CHB was slightly increased, but TNF-α production seemed to be decreased compared with that in healthy controls. The expression of some activation markers varied among children with different phases of CHB, especially the higher CD38 expression found on T cells in the IA phase. Regression analysis revealed that IFN-γ and TNF-α production by NK cells and CD8+ T cells seemed to have positive correlations with ALT elevation and an activated status of NK cells or T cells.Conclusion: NK cells and T cells tended to be phenotypically activated (especially in the IA phase) in children with CHB compared with healthy controls. However, their cytokine-producing function was not obviously elevated, especially IFN-γ production by CD8+ T cells. More studies investigating the mechanism and observing the longitudinal changes in the immune status in children with CHB are needed.

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Circulating cytokines and lymphocyte subsets in patients who have recovered from COVID-19

10.1101/2020.07.22.20160259 ◽

2020 ◽

Author(s):

Hasi Chaolu ◽

Xinri Zhang ◽

Xin Li ◽

Dongyan Li

Keyword(s):

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lymphocyte Subsets ◽

Healthy Controls ◽

Tnf Α ◽

Ifn Γ ◽

Circulating Cytokines

To investigate the immune status of people who previously had COVID-19 infections, we recruited patients 2 weeks post-recovery and analyzed circulating cytokines and lymphocyte subsets. We measured levels of total lymphocytes, CD4+ T cells, CD8+ T cells, CD19+ B cells, CD56+ NK cells, and the serum concentrations of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-10, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) by flow cytometry. We found that in most post-recovery patients, levels of total lymphocytes (66.67%), CD3+ T cells (54.55%), CD4+ T cells (54.55%), CD8 + T cells (81.82%), CD19+ B cells (69.70%), and CD56+ NK cells(51.52%) remained lower than normal, whereas most patients showed normal levels of IL-2 (100%), IL-4 (80.88%), IL-6 (79.41%), IL-10 (98.53%), TNF-α (89.71%), IFN-γ (100%) and IL-17 (97.06%). Compared to healthy controls, 2-week post-recovery patients had significantly lower absolute numbers of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells, along with significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17. Among post-recovery patients, T cells, particularly CD4+ T cells, were positively correlated with CD19+ B cell counts. Additionally, CD8+ T cells positively correlated with CD4+ T cells and IL-2 levels, and IL-6 positively correlated with TNF-α and IFN-γ. These correlations were not observed in healthy controls. By ROC curve analysis, post-recovery decreases in lymphocyte subsets and increases in cytokines were identified as independent predictors of rehabilitation efficacy. These findings indicate that the immune system has gradually recovered following COVID-19 infection; however, the sustained hyper-inflammatory response for more than 14 days suggests a need to continue medical observation following discharge from the hospital. Longitudinal studies of a larger cohort of recovered patients are needed to fully understand the consequences of the infection.

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Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

10.21203/rs.2.11667/v2 ◽

2019 ◽

Author(s):

Yurong Gu ◽

Yifan Lian ◽

Qiaolan Zheng ◽

Zexuan Huang ◽

Lin Gu ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Natural Killer ◽

Chronic Hepatitis B ◽

Cd8 T Cells ◽

Nkt Cells ◽

Adaptive Immune ◽

Tnf Α ◽

Ifn Γ

Abstract Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune system. This study aimed to identify the relationship between antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells in a cohort of chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results IFN-γ+ and TNF-α+ by CD4+ and CD8+ T cells were significantly higher in immune active (IA) than other phases. Immune tolerant (IT) patients showed the least expression of IFN-γ+ by NK and NKT cells, and TNF-α+ by NK cells. IFN-γ+, TNF-α+ and IL-2+ by CD4+ and CD8+ T cells were comparable between IA and gray zones (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differ from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ+ and TNF-α+, but not IL-2+, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ by NKT cells was associated with HBV DNA, while IFN-γ+ by CD4+ and CD8+ T cells had correlation with age. Conclusion HBV clinical phases are characterized by distinct cytokines signatures, which showed little relationship to viral features at a single time point in these untreated CHB patients.

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Circulating Cytokines and Lymphocyte Subsets in Patients Who Have Recovered from COVID-19

BioMed Research International ◽

10.1155/2020/7570981 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Hasichaolu ◽

Xinri Zhang ◽

Xin Li ◽

Dongyan Li

Keyword(s):

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Lymphocyte Subsets ◽

Healthy Controls ◽

Cell Counts ◽

Tnf Α ◽

Ifn Γ

To investigate the immune status of people who previously had COVID-19 infections, we recruited two-week postrecovery patients and analyzed circulating cytokine and lymphocyte subsets. We measured levels of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells and the serum concentrations of interleukin- (IL-) 1, IL-4, IL-6, IL-8, IL-10, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) by flow cytometry. We found that in most postrecovery patients, levels of total lymphocytes (66.67%), CD3+ T cells (54.55%), CD4+ T cells (54.55%), CD8+ T cells (81.82%), CD19+ B cells (69.70%), and CD56+ NK cells (51.52%) remained lower than normal, whereas most patients showed normal levels of IL-2 (100%), IL-4 (80.88%), IL-6 (79.41%), IL-10 (98.53%), TNF-α (89.71%), IFN-γ (100%), and IL-17 (97.06%). Compared to healthy controls, two-week postrecovery patients had significantly lower absolute numbers of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells, along with significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17. Among postrecovery patients, T cells, particularly CD4+ T cells, were positively correlated with CD19+ B cell counts. Additionally, CD8+ T cells were positively correlated with CD4+ T cells and IL-2 levels, and IL-6 positively correlated with TNF-α and IFN-γ. These correlations were not observed in healthy controls. By ROC curve analysis, postrecovery decreases in lymphocyte subsets and increases in cytokines were identified as independent predictors of rehabilitation efficacy. These findings indicate that the immune system gradually recovers following COVID-19 infection; however, the sustained hyperinflammatory response for more than 14 days suggests a need to continue medical observation following discharge from the hospital. Longitudinal studies of a larger cohort of recovered patients are needed to fully understand the consequences of the infection.

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Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

10.21203/rs.2.11667/v1 ◽

2019 ◽

Author(s):

Yurong Gu ◽

Yifan Lian ◽

Qiaolan Zheng ◽

Zexuan Huang ◽

Lin Gu ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Natural Killer ◽

Chronic Hepatitis B ◽

Cd8 T Cells ◽

Nkt Cells ◽

Adaptive Immune ◽

Tnf Α ◽

Ifn Γ

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Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

10.21203/rs.2.11667/v3 ◽

2020 ◽

Author(s):

Yurong Gu ◽

Yifan Lian ◽

Qiaolan Zheng ◽

Zexuan Huang ◽

Lin Gu ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Hepatitis B ◽

Natural Killer ◽

Chronic Hepatitis B ◽

Cd8 T Cells ◽

Nkt Cells ◽

Adaptive Immune ◽

Tnf Α ◽

Ifn Γ

Abstract Background: Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods: We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results: levels of IFN-γ + and TNF-α + CD4 + and CD8 + T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ + , TNF-α + and IL-2 + CD4 + and CD8 + T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ + NKT cells were associated with HBV DNA, while IFN-γ + CD4 + and CD8 + T cells were correlated with age. Conclusion : HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.

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CD8+CD28− T cells: key cytotoxic players impacting disease pathogenesis in chronic HBV infection

Clinical Science ◽

10.1042/cs20190369 ◽

2019 ◽

Vol 133 (17) ◽

pp. 1917-1934

Author(s):

Madhuparna Nandi ◽

Sourina Pal ◽

Sumantra Ghosh ◽

Bidhan Chandra Chakraborty ◽

Debangana Dey ◽

...

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

T Cell ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Hepatitis B E Antigen ◽

Tnf Α ◽

Ifn Γ

Abstract During chronic hepatitis B (CHB), CD8+ T cells down-regulate CD28, the primary co-stimulation molecule for T-cell activation. Diverse functional attributes of CD8+CD28− T cells are suggested in various disease contexts. The present study aimed to characterize CD8+CD28− T cells in different phases of chronic Hepatitis B virus (HBV) infection (CHI)- Immune-tolerance (IT), Hepatitis B e-antigen-positive CHB (EP-CHB), Inactive carriers (IC) and Hepatitis B e-antigen-negative CHB (EN-CHB), to appraise their contribution in HBV-related disease pathophysiology. Flow cytometry analysis of T cells in peripheral blood of study subjects revealed enhanced CD8+CD28− T-cell accumulation in EP-/EN-CHB, compared with IT/IC and they expanded equivalently in HBV-specific and non-specific CD8+ T-cell compartments. Profound increase in CD8+CD28− T cells expressing perforin/granzyme-B/CD57/IFN-γ/TNF-α and markers of terminal differentiation were observed exclusively in EP-/EN-CHB. Further, activation with anti-NKG2D resulted in heightened IFN-γ/TNF-α production selectively from CD8+CD28− T cells, suggesting NKG2D-mediated alternative co-stimulation. CD8+CD28− T cells sorted from CHB patients induced enhanced apoptosis of peripheral blood mononuclear cells (PBMC), including CD4+ T cells. However, NKG2D-ligand (major histocompatibility complex class I chain-related molecule A/B (MICA/B)) was preferentially expressed by HBV-specific CD4+ T cells of CHB patients, making these cells a potential target to NKG2D-dependent CD8+CD28− T-cell killing. Both CD28+ and CD28− T cells in CHB expressed CXCR3 at similar levels and thus capable of homing to the liver. A positive correlation was seen between CD8+CD28− T-cell frequency and serum-alanine transaminase (ALT) levels and CHB-derived CD8+CD28− T cells caused pronounced cell death in HBV-transfected Huh7 cells. Immunofluorescence staining identified greater intrahepatic incidence of CD8+CD28− T cells but decline in CD4+ T cells in CHB than IC. Collectively, CD8+CD28− T cells demonstrated differential distribution and phenotypic/functional skewing in different CHI phases and contribute to disease progression by Perforin-Granzyme- or IFN-γ-TNF-α-mediated cytotoxicity while restraining antiviral immunity through NKG2D-dependent HBV-specific CD4+ T-cell depletion.

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775 CHARACTERISING THE IMMUNE STATUS OF HBV-SPECIFIC CD4– AND CD8– T-CELLS PRODUCING IL-17 IN PATIENTS WITH CHRONIC HEPATITIS B (CHB) VIRUS INFECTION

Journal of Hepatology ◽

10.1016/s0168-8278(12)60788-0 ◽

2012 ◽

Vol 56 ◽

pp. S304

Author(s):

H. Cooksley ◽

A. Riva ◽

M. Simonova ◽

K. Katzarov ◽

S. Chokshi

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Virus Infection ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Cd8 T Cells ◽

Immune Status

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PMO-152 Characterising the immune status of HBV-specific CD4+ and CD8+ T-cells producing IL-17 in patients with chronic hepatitis B (CHB) virus infection

Gut ◽

10.1136/gutjnl-2012-302514b.152 ◽

2012 ◽

Vol 61 (Suppl 2) ◽

pp. A135.1-A135

Author(s):

H Cooksley ◽

A Riva ◽

M Simonova ◽

K Katzarov ◽

S Chokshi

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Virus Infection ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Cd8 T Cells ◽

Immune Status

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Reduced frequency of perforin-positive CD8+ T cells in menstrual effluent of endometriosis patients compared to healthy controls

10.1101/2020.12.03.20243436 ◽

2020 ◽

Author(s):

Timo Schmitz ◽

Verena Hoffmann ◽

Elisabeth Olliges ◽

Alina Bobinger ◽

Roxana Popovici ◽

...

Keyword(s):

T Cells ◽

Cell Adhesion ◽

Nk Cells ◽

Adhesion Molecules ◽

Cd8 T Cells ◽

Cell Adhesion Molecules ◽

Nk Cell ◽

Control Group ◽

Healthy Controls ◽

Tnf Α

AbstractBackgroundEndometriosis is a widespread disease in women of reproductive age. The disease often reduces life quality of women affected by symptoms like dysmenorrhea, dyspareunia or infertility. Diagnosis remains challenging and no causal treatments exist until now. The scientific literature indicates many immunological changes like reduced cytotoxicity of natural killer cells and macrophages or altered concentrations of cytokines or cell adhesion molecules in women with endometriosis. Research has been concentrated on immunological alterations in peripheral blood, endometrial tissue and peritoneal fluid of women with endometriosis. Yet, knowledge on immunological differences in menstrual effluent is scarce. The aim of this study was to investigate menstrual effluent of hormone-free women with endometriosis in comparison to age matched healthy controls regarding selected immunological parameters.Methods12 women with endometriosis and 11 healthy controls were included in the study. Menstrual effluent (ME) was collected using menstrual cups over a time period of 24 h, and venous blood samples (PB) were taken. Mononuclear cells were obtained from ME (MMC) and PB (PBMC) using density gradient centrifugation and analyzed using flow cytometry. Furthermore, concentrations of cell adhesion molecules (ICAM-I and VCAM-I) and cytokines (IL-6, IL-8 and TNF-α) were measured in centrifugation supernatant of ME and plasma of PB.ResultsThe comparison of MMC from women with endometriosis and healthy controls revealed a significantly lower frequency of perforin-positive cells among CD8+ T cells in endometriosis patients compared to healthy controls. No additional differences regarding frequencies of CD8+ or CD4+ T cells, regulatory T cells (Tregs), NK cell subsets or monocytic subsets could be detected between MMC or PBMC, of endometriosis patients and healthy controls. Comparing MMC with PBMC revealed that MMC contained significantly more B cells and significantly less T cells than PBMC. Among the T cells, the CD4/CD8 ratio was significantly higher in MMC, and Tregs were significantly less common in MMC. T cells and NK cells expressed significantly more CD69 in MMC., NK cells of the MMC were predominantly CD56bright/CD16dim and the CD56dim NK cell subset had a low frequency of perforin+ cells, in contrast to CD56dim NK cells of PBMC, which were predominantly perforin-positive. However, NKp46 was significantly more expressed on NK cells from MMC. Finally, the endometriosis group had significantly lower plasma ICAM-I concentrations than the control group. There were no significant differences in VCAM-1, IL-6, IL-8 or TNF-α between the two groups.ConclusionMMC are distinctively different from PBMC and, thus, seem to be of endometrial origin. The CD8+ T cells from the ME were significantly less perforin-positive in endometriosis patients than in healthy controls, suggesting a reduced cytotoxic potential.

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