CD8 + CD28 - T细胞：影响慢性HBV感染疾病发病机制的关键细胞

StephenW

CD8 + CD28 - T-cells: Key cytotoxic players impacting disease pathogenesis in chronic HBV infection; Nandi M, Pal S, Ghosh S, Chakraborty B, Dey D, Baidya A, Shil A, Chattopadhyaya S, Banerjee S, Santra A, Chowdhury A, Datta S; Clinical Science (London, England : 1979) (2019)

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        Hepatitis

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During chronic hepatitis B (CHB), CD8 + T-cells downregulate CD28, the primary costimulation 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 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 to 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 PBMC, including CD4 + T-cells. However, NKG2D-ligand (MICA/B) was preferentially expressed by HBV-specific CD4 + T-cells of CHB patients, making these cells a potential target to NKG2D-dependant 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-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 cytotoxicty while restraining antiviral immunity through NKG2D-dependant HBV-specific CD4 + T-cell depletion.

StephenW

CD8 + CD28  -  T细胞：影响慢性HBV感染疾病发病机制的关键细胞毒性参与者; Nandi M，Pal S，Ghosh S，Chakraborty B，Dey D，Baidya A，Shil A，Chattopadhyaya S，Banerjee S，Santra A，Chowdhury A，Datta S;临床科学（伦敦，英国：1979）（2019）

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肝炎

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在慢性乙型肝炎（CHB）期间，CD8 + T细胞下调CD28，CD28是T细胞活化的主要共刺激分子。 CD8 + CD28  -  T细胞的多种功能属性在各种疾病背景下被提出。本研究旨在表征慢性HBV感染（CHI）不同阶段的CD8 + CD28  -  T细胞 - 免疫耐受（IT），乙型肝炎e抗原阳性CHB（EP-CHB），非活性载体（IC）和乙型肝炎e抗原阴性CHB（EN-CHB），以评估他们在HBV相关疾病病理生理学中的贡献。与IT / IC相比，研究对象的外周血中T细胞的流式细胞术分析显示EP8 / CD-T细胞在EP- / EN-CHB中的积累增强，并且它们在HBV特异性和非特异性CD8 +中等效扩增T细胞区室。 CD8 + CD28的显着增加 - 表达穿孔素/颗粒酶-T / CD57 / IFN-γ/ TNF-α的T细胞和终末分化的标志物仅在EP- / EN-CHB中观察到。此外，用抗-NKG 2D激活导致从CD8 + CD28-T细胞中选择性地增加IFN-γ/ TNF-α的产生，表明NKG2D介导的替代共刺激。从CHB患者分选的CD8 + CD28-T细胞诱导PBMC的增强的凋亡，包括CD4 + T细胞。然而，NKG2D配体（MICA / B）优先由CHB患者的HBV特异性CD4 + T细胞表达，使这些细胞成为NKG2D依赖性CD8 + CD28  -  T细胞杀伤的潜在靶标。 CHB中的CD28 +和CD28-T细胞均以相似的水平表达CXCR3，因此能够归巢至肝脏。 CD8 + CD28  -  T细胞频率与血清ALT水平呈正相关，而CHB衍生的CD8 + CD28  -  T细胞在HBV转染的Huh7细胞中引起明显的细胞死亡。免疫荧光染色鉴定出CD8 + CD28  -  T细胞的肝内发病率较高，但CHB中CD4 + T细胞的下降比IC低。总的来说，CD8 + CD28  -  T细胞在不同的CHI期显示出差异分布和表型/功能倾斜，并且通过穿孔素 - 颗粒酶 - 或IFN-γ-TNF-α介导的细胞毒性促进疾病进展，同时通过NKG2D抑制抗病毒免疫 - 依赖性HBV特异性CD4 + T细胞耗竭。