gamma delta T cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of... Show moregamma delta T cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how gamma delta T-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8 alpha-dependent V gamma 5V delta 1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of gamma delta TCRs, we show that classic anti-HLA-directed, gamma delta TCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive gamma delta T-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual gamma delta TCRs for genetic engineering of tumor-reactive T cells. Show less
Hepatitis C Virus (HCV) is a major public health concern, with no effective vaccines currently available and 3% of the world's population being infected. Despite the existence of both B-and T-cell... Show moreHepatitis C Virus (HCV) is a major public health concern, with no effective vaccines currently available and 3% of the world's population being infected. Despite the existence of both B-and T-cell immunity in HCV-infected patients, chronic viral infection and HCV-related malignancies progress. Here we report the identification of a novel HCV TCR from an HLA-A2-restricted, HCV NS3:1073-1081-reactive CTL clone isolated from a patient with chronic HCV infection. We characterized this HCV TCR by expressing it in human T cells and analyzed the function of the resulting HCV TCR-transduced cells. Our results indicate that both the HCV TCR-transduced CD4(+) and CD8(+) T cells recognized the HCV NS3:1073-1081 peptide-loaded targets and HCV+ hepatocellular carcinoma cells (HCC) in a polyfunctional manner with cytokine (IFN-gamma, IL-2, and TNF-alpha) production as well as cytotoxicity. Tumor cell recognition by HCV TCR transduced CD8(-) Jurkat cells and CD4(+) PBL-derived T cells indicated this TCR was CD8-independent, a property consistent with other high affinity TCRs. HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections. Show less
