PD-1 Expression In CD8 Research Articles

CD4+CD25+CD127(low) Regulatory T Cells Play Predominant Anti-Tumor Suppressive Role in Hepatitis B Virus-Associated Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide and hepatitis B is one of the commonest causes. T regulatory cells (Tregs) are strong immunomodulators and are likely to play a major role in HCC development. HBV infection is reported to induce expansion of Tregs. We investigated the CD4+CD25+CD127−veFoxP3+ Tregs in HBV-related HCC as compared to non-HBV-HCC.Patients and Methods: Whole blood immunophenotyping was analyzed by multicolor flow cytometry in patients with HBV-related HCC (HBV-HCC, n = 17), non-HBV-HCC (n = 22; NASH = 16, alcohol-related = 6), and chronic hepatitis B infection (CHBV; n = 10). Tregs functionality was checked by in vitro suppression assays using CD4+ CD25+ CD127low Tregs. Levels of serum alpha-fetoprotein (AFP), expression of FoxP3, IL-10, PD1, TGF-β, and Notch in Tregs, and liver explants were analyzed by flow cytometry, immunohistochemistry, and quantitative RT-PCR.Results: CD4+CD25+hi and Foxp3 expression in CD4+CD25+hiCD127low was significantly increased (P = 0.04, P = 0.007) in HBVHCC compared to non-HBVHCC and CHBV patients. HBVHCC also showed high IL-10 and TGF-β secreting CD4 + CD25 + hiTregs. The PD1 expression in CD4 + CD25+hi was significantly decreased in the HBVHCC than non-HBVHCC. In HBVHCC, AFP levels were significantly high (median 941, range 2–727940) than non-HBVHCC (median 13.5, range 2–18,900). In HBVHCC, patients with high AFP (range; 3982–727940 ng/ml) showed positive correlation with Foxp3 expression in CD4+CD25+hi CD127low (r = 0.857, P = 0.014). Reduced PD1 expression in HBVHCC also had negative correlation with FOXP3 in CD4+CD25+hi CD127low (r = −0.78, P = 0.04). However, AFP levels in non-HBVHCC showed negative correlation with (R = −0.67, P = 0.005) with CD4+CD25+hi Tregs.Conclusion: Our results demonstrate that CD4+ CD25+hi Tregs from HBVHCC patients have decreased expression of PD1, resulting in higher IL-10 and TGF-β secretion. Increased suppressive ability of Tregs in HBV-related HCC confers increased anti-tumor suppressive response than in non-HBV-HCC. Modulation of Tregs and PD1 may serve as useful therapeutic targets.

USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity.

BackgroundInterferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown.MethodIn this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice.ResultsEctopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy.ConclusionThese findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.

Vaccination with Leishmania mexicana LPG induces PD-1 in CD8+ and PD-L2 in macrophages thereby suppressing the immune response: A model to assess vaccine efficacy

Leishmania lipophosphoglycan (LPG) is a molecule that has been used as a vaccine candidate, with contradictory results. Since unsuccessful protection could be related to suppressed T cell responses, we analyzed the expression of inhibitory receptor PD-1 in CD8+ and CD4+ lymphocytes and it is ligand PD-L2 in macrophages of BALB/c mice immunized with various doses of Leishmania mexicana LPG and re-stimulated in vitro with different concentrations of LPG. Vaccination with LPG enhanced the expression of PD-1 in CD8+ cells. Activation molecules CD137 were reduced in CD8+ cells from vaccinated mice. In vitro re-stimulation enhanced PD-L2 expression in macrophages of healthy mice in a dose-dependent fashion. The expression of PD-1, PD-L2 and CD137 is modulated according to the amount of LPG used during immunization and in vitro re-stimulation. We analyzed the expression of these molecules in mice infected with 1×104 or 1×105L. mexicana promastigotes and re-stimulated in vitro with LPG. Infection with 1×105 parasites increased the PD-1 expression in CD8+ and diminished PD-L2 in macrophages. When these CD8+ cells were re-stimulated in vitro with LPG, simulating a second exposure to parasite antigens, PD-1 expression increased significantly more, in a dose dependent fashion. We conclude that CD8+ T lymphocytes and macrophages express inhibition molecules according to the concentrations of Leishmania LPG and to the parasite load. Vaccination with increased amounts of LPG or infections with higher parasite numbers induces enhanced expression of PD-1 and functional inactivation of CD8+ cells, which can have critical consequences in leishmaniasis, since these cells are crucial for disease control. These results call for pre-vaccination evaluations of potential immunogens, specifically where CD8 cells are required, since inhibiting molecules can be induced after certain thresholds of antigen concentrations. We propose that the analysis of PD-1 and PD-L2 are useful tools to monitor the optimal dose for vaccination candidates.

328 PROGRAMMED DEATH 1 (PD-1) EXPRESSION OF PERIPHERAL CD4+ T LYMPHOCYTES IMPLICATES PROGRESSION OF MALNUTRITION AND HEPATIC CARCINOGENESIS IN PERSISTENT HEPATITIS C VIRAL INFECTION

Background and Aims: Persistent HCV infection leads to liver fibrosis and carcinogenesis. Expression of PD-1, an inhibitory molecule, causes T cell exhaustion and failure of HCV eradication. Furthermore, degree of PD-1 expression defines the level of T cell dysfunction (Nakamoto N et al. Gastroenterology 2008. 134: p1927–37). However, little is known about how persistent T cell exhaustion influences clinically during HCV infection. Methods: Sixty patients of chronic hepatitis C were included. Peripheral blood mononuclear cells were taken after informed consent, and were analyzed by flow cytometry before intervention. Twenty-two patients (37%) were HCC-bearing cases. Clinical laboratory parameters including serum albumin, branch-chain amino acids (BCAA) to tyrosine ratio (BTR), cross-section area of visceral fat (by electrode impedance method), METAVIR staging of recent liver biopsy (available in 29 cases), and clinical staging of HCC were also analyzed. Results: PD-1 expression of peripheral CD4 T lymphocytes was significantly elevated in HCC-bearing cases (12.1% vs 7.4%, p < 0.0001), but that of peripheral CD8 T lymphocytes was not statistically significant. To further evaluate risk factors affecting hepatic carcinogenesis, we found that PD-1 expression of CD4 T lymphocytes had no statistical correlation to fibrosis stages of liver biopsy specimen (p =0.98). Elevated PD-1 expression of CD4 T lymphocytes significantly correlated to lower serum albumin (p < 0.0001, correlation coefficient c.c.= −0.49), lower BTR (excluding BCAA supplemented cases, p = 0.016, c.c.= −0.48), and higher crosssection area of visceral fat to body surface area (BSA) ratio (p = 0.0016, c.c.= 0.55), which suggested that T cell dysfunction significantly correlated to nutritional/metabolic derangements in chronic hepatitis C. PD-1 expression of CD4+ T lymphocytes also increased accordingly to the T factor of HCC (p =0.035), TNM staging (p = 0.015), and JIS scores (p = 0.013). Furthermore, PD-L2 levels expressed on plasmacytoid dendritic cells (pDCs) were significantly increased as PD-1 expression of CD4+ T lymphocytes elevated (p =0.002, c.c.= 0.61). Conclusions: These findings suggest that T cell exhaustion may play a pathological role in carcinogenesis and HCC progression in chronic HCV infection. Correlation of PD-1 expression of CD4+ T lymphocytes and nutritional/metabolic factors also suggests an immunological rationale for nutritional intervention in these patients.

P252 PD-1 Expression on Human Lung T Cells in Health and COPD

Introduction and ObjectivesPatient s with chronic obstructive pulmonary disease (COPD) are susceptible to the effects of recurrent respiratory infections despite increased numbers of CD8+ T cells in the lungs. We...

Research of PD-1 expression in CD8+ T cell of peripheral blood with HBV-associated acute-on-chronic liver failure

To analyze PD-1 expression in CD8 + T cell of Peripheral blood with HBV-associated acute-on-chronic liver failure and effect on CD8+ T cell. We selected 60 patients with HBV-ACLF and collected their peripheral blood. We analyzed the expressions of PD-1, CD95, perforin, granzyme A, granzyme B, CD107a on CD8+ T lymphocytes and the expression of PD-L1 on monocytes peripheral blood by using flow cytometry. 15 liver cirrhosis patients( LC) and 15 healthy individuals( HC) are control groups. PD-1 expression was (1) The PD-1 expression in HBV-ACLF patients was significantly elevated compared with those in HC and lower in improved group than that in invalid group and death group (P < 0.05) and increased from prophase, metaphase to advanced stage (P < 0.05). Moreover, (2) PD-L1 expression on monocytes was positively correlated with disease progression. (P < 0.05). (3) Both PD-1 and CD95 expressions were higher in dead group than those in improved and non-improved groups. Perforin, granzymes and CD107a expressions on CD8+ T cells significantly increased in dead group compared with those in improved and non-improved groups (P < 0.05). However, PD-1 expressions on these cells were lower, compared with normal persons. The expression of PD-1 and PD-L1 in HBV-ACLF patients was positively correlated with disease progression. The elevated PD-1 expression promoted apoptosis of CD8+ T cells. For HBV-ACLF patients, the PD-1 expression on effector CD8+ T cells was lower than those in other CD8+ T cells, which maybe accounted for the failure to controlling immune injury in liver.