The most common human viruses have different abilities to establish persistent chronic infection. Virus-specific T-cell responses are critical in the control of virus replication and in the prevention of disease in chronic infection. A large number of phenotypic markers and a series of functions have been used to characterize virus-specific CD4+ and CD8+ T-cell responses, and these studies have shown great phenotypic and functional heterogeneity of the T-cell responses against different viruses. The heterogeneity of the T-cell response has been proposed to be specific to each virus. However, over the past 2 years, several studies have provided evidence that the phenotypic and functional heterogeneity of CD4+ and CD8+ T-cell responses is predominantly regulated by the levels of antigen load. The levels of antigen load modulate the phenotypic and functional patterns of the T-cell response within the same virus infection. Furthermore, the functional characterization of virus-specific CD4+ and CD8+ T-cell responses has identified signatures of protective antiviral immunity. Polyfunctional, i.e. interleukin-2 and interferon-gamma (IFN-gamma) secretion and proliferation, and not monofunctional, i.e. IFN-gamma secretion, CD4+ and CD8+ T-cell responses represent correlates of protective antiviral immunity in chronic virus infections.
Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8(+) T cells in vitro. In vivo, glioblastoma-specific CD8(+) T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastoma.
Some cancer patients mount spontaneous T- and B-cell responses against their tumor cells. Autologous tumor reactive CD8 cytolytic T lymphocyte (CTL) and CD4 T-cell clones as well as antibodies from these patients have been used for the identification of genes encoding the target antigens. This knowledge opened the way for new approaches to the immunotherapy of cancer. In this review, we describe the characterization of the structure-function properties of the melanocyte/melanoma tumor antigen Melan-A/MART-1, the assessment of the T-cell repertoire available against this antigen in healthy individuals, and the analysis of naturally acquired and/or vaccine-induced CTL responses to this antigen in patients with metastatic melanoma.
In the early events of human immunodeficiency virus type 1 (HIV-1
HCV infection has a severe course of disease in HIV/HCV co-infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV-specific T-cell responses in 86 HCV mono-infected patients, 48 HIV/HCV co-infected patients and 42 liver transplant recipients. IFN-c and IL-2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCVderived peptides. We observed that HCV-specific T-cell responses were polyfunctional in HCV mono-infected patients, with presence of proliferating single IL-2-, dual IL-2/IFN-c and single IFN-c-producing CD4 1 and dual IL-2/IFN-c and single IFN-c-producing CD8 1 cells. In contrast, HCV-specific T-cell responses had an effector profile in HIV/HCV coinfected individuals and liver transplant recipients with absence of single IL-2-producing HCV-specific CD4 1 and dual IL-2/IFN-c-producing CD8 1 T cells. In addition, HCV-specific proliferation of CD4 1 and CD8 1 T cells was severely impaired in HIV/HCV co-infected patients and liver transplant recipients. Importantly, ''only effector'' T-cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores.Ã These two authors contributed equally to this work. Therefore, the present results suggest that immune-based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV-1 co-infection and liver transplantation.
The specificity of recognition of pMHC complexes by T lymphocytes is determined by the V regions of the TCR α- and β-chains. Recent experimental evidence has suggested that Ag-specific TCR repertoires may exhibit a more Vα- than Vβ-restricted usage. Whether Vα usage is narrowed during immune responses to Ag or if, on the contrary, restricted Vα usage is already defined at the early stages of TCR repertoire selection, however, has remained unexplored. Here, we analyzed V and CDR3 TCR regions of single circulating naive T cells specifically detected ex vivo and isolated with HLA-A2/melan-A peptide multimers. Similarly to what was previously observed for melan-A-specific Ag-experienced T cells, we found a relatively wide Vβ usage, but a preferential Vα 2.1 usage. Restricted Vα 2.1 usage was also found among single CD8+ A2/melan-A multimer+ thymocytes, indicating that Vα-restricted selection takes place in the thymus. Vα 2.1 usage, however, was independent from functional avidity of Ag recognition. Thus, interaction of the pMHC complex with selected Vα-chains contributes to set the broad Ag specificity, as underlined by preferential binding of A2/melan-A multimers to Vα 2.1-bearing TCRs, whereas functional outcomes result from the sum of these with other interactions between pMHC complex and TCR.
In human gliomas, self-renewing and tumor-initiating cells are characterized by the expression marker CD133. Although, widely used, the validity of CD133 is debated as recent data show that CD133 1 and CD133 2 cells share similar stemness and tumorigenic properties. To clarify this ''CD133 controversy'', we reexamined the methods of purification and the stem behavior of both CD133 compartments in fresh gliomas and gliomasphere cultures. Using human anti-CD133-coupled microbeads and magnetic activated cell sorting, we observed a nonspecific sorting of glioma cells irrespective of their CD133 expression. In contrast, when purified by fluorescence activating cell sorting, a specific expression and enrichment of CD133 was successfully observed in fresh human gliomas and gliomasphere cultures. However, neither the expression of stemness genes nor the long-term self-renewal capacities of CD133 1 and CD133 2 cells were significantly different, even after fresh isolation. Altogether, our data show that purification of CD133 1 glioma cells using hCD133-microbeads presents a lack of specificity and demonstrate that the use of CD133 as a unique glioma stem cell marker is likely not sufficient to tag the whole self-renewing tumor cell reservoir. ' UICCKey words: AC133 antigen; brain tumor; glioma self-renewing cells; stem cell markerThe human prominin-1/CD133 protein has recently gained attention as a cell surface marker to isolate human embryonic neural stem cells and tumor-initiating cells (TICs).1-4 When isolated from human brain tumors, CD1331 cells display stem cell properties in vitro and initiate tumor growth in vivo.1,2 However, compelling studies report that some CD133 2 glioma cells share similar properties with CD133 1 cells, including self-renewal and tumorigenicity, suggesting that CD133 is insufficient to fully define TICs.5-8 Nonetheless, it remains accepted that CD133 is the only available marker and nearly the whole body of published work attempting to characterize TICs in gliomas is based on the use of CD133. Here, we reexamined the use and the relevance of CD133 as a marker of self-renewing cells in human gliomas by comparing the magnetic activated cell sorting (MACS) vs. fluorescence activating cell sorting (FACS) sorting methodologies, technically and functionally. 1,2,[5][6][7][8] Material and methods Human specimen processing, gliomasphere cultures, limiting dilution assays and statistic toolPeripheral blood mononuclear cells (PBMCs) and primary brain tumors were obtained following approved protocol by the ethical committee. Tumor processing, cell cultures and secondary spheres assays were done as described in Refs. 3 and 9. Briefly, the tumour was chopped and digested with papain. The spherogenic capacity of purified CD133 1 and CD133 2 single cells after fresh isolation or from enriched stem cell cultures was tested by limiting dilution (1 cell/ll) and determined by quantifying the number of primary spheres and secondary spheres. The long-term self-renewal ability of individual clones was followed...
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