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.作者: StephenW 时间: 2019-9-11 14:25