Dysfunctional CD8؉ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8؉ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.Quantitative and qualitative impairments of virus-specific T cells are present in different chronic viral infections, in both humans and mice. The persistent exposure to viral antigens can lead to virus-specific T-cell deletion or to progressive functional impairment. Recent data show that these exhausted T cells hyperexpress the programmed death 1 (PD-1) molecule (8,14,19,23) and that blocking the engagement of PD-1 with its ligand (PD-L1) leads to an enhancement of the antiviral functions of these T cells (1,7,23,30,32). The characterization of the functional defects of virus-specific T cells in patients with chronic hepatitis B virus (HBV) infection, a condition that affects 350 million people worldwide, is still largely incomplete and often based on an oversimplified dichotomy between patients who control acute infection and subjects with established chronicity. While it is well documented that patients who succeed in resolving HBV infection express a vigorous and functionally efficient HBV-specific T-cell response (9,12,13,15,21,29), the degree of HBV-specific T-cell impairments which affect chronically infected patients has so far been only partially analyzed with small groups of patients by using a limited set of well-characterized HLA-A2-restricted epitopes (3,18,21,25,27,28,34) or by focusing mainly on HLA class II-restricted responses targeting HBV structural antigens (9, 11-13, 17, 26, 31).To overcome these limitations, we performed a longitudinal study of HBV-specific T-cell responses by using pools of overlapping peptide...
The molecular and cellular basis of long-term T cell memory against viral antigens is still largely undefined. To characterize anti-viral protection by memory T cells against non-cytopathic viruses able to cause acute self-limited and chronic infections, such as the hepatitis B virus (HBV), we studied HLA class II restricted responses against HBV structural antigens in 17 patients with acute hepatitis B, during the acute stage of infection and 2.2 to 13 yr after clinical resolution of disease. Results indicate that: (a) significant T cell proliferative responses to HBV nucleocapsid antigens were detectable in all patients during the acute phase of infection and in 14/17 also 2-13 yr after clinical resolution of disease; b) long-lasting T cell responses were sustained by CD45RO ϩ T cells, predominantly expressing the phenotype of recently activated cells; c) limiting dilution analysis showed that in some patients the frequency of HBV-specific T cells was comparable to that observed in the acute stage of infection and, usually, higher than in patients with chronic HBV infection; d) the same amino acid sequences were recognized by T cells in the acute and recovery phases of infection; and e) HBV-DNA was detectable by nested-PCR in approximately half of the subjects.In conclusion, our results show that vigorous anti-viral T cell responses are detectable in vitro several years after clinical recovery from acute hepatitis B. Detection of minute amounts of virus in some recovered subjects suggests that long-term maintenance of an active anti-viral T cell response could be important not only for protection against reinfection but also for keeping the persisting virus under tight control. ( J. Clin. Invest. 1996. 98:1185-1194.)
Key Points• Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression.• Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138 1 cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138 1 cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138 1 cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM. (Blood. 2016;128(5):667-679)
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