Binding of TCR Multimers and a TCR-Like Antibody with Distinct Fine-Specificities Is Dependent on the Surface Density of HLA ComplexesReportar como inadecuado




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Class I Major Histocompatibility Complex MHC molecules evolved to sample degraded protein fragments from the interior of the cell, and to display them at the surface for immune surveillance by CD8+ T cells. The ability of these lymphocytes to identify immunogenic peptide-MHC pMHC products on, for example, infected hepatocytes, and to subsequently eliminate those cells, is crucial for the control of hepatitis B virus HBV. Various protein scaffolds have been designed to recapitulate the specific recognition of presented antigens with the aim to be exploited both diagnostically e.g. to visualize cells exposed to infectious agents or cellular transformation and therapeutically e.g. for the delivery of drugs to compromised cells. In line with this, we report the construction of a soluble tetrameric form of an αβ T cell receptor TCR specific for the HBV epitope Env183–191 restricted by HLA-A*02:01, and compare its avidity and fine-specificity with a TCR-like monoclonal antibody generated against the same HLA target. A flow cytometry-based assay with streptavidin-coated beads loaded with Env183–191-HLA-A*02:01 complexes at high surface density, enabled us to probe the specific interaction of these molecules with their cognate pMHC. We demonstrate that the TCR tetramer has similar avidity for the pMHC as the antibody, but they differ in their fine-specificity, with only the TCR tetramer being capable of binding both natural variants of the Env183–191 epitope found in HBV genotypes A-C-D 187Arg and genotype B 187Lys. Collectively, the results highlight the promiscuity of our soluble TCR, which could be an advantageous feature when targeting cells infected with a mutation-prone virus, but that binding of the soluble oligomeric TCR relies considerably on the surface density of the presented antigen.



Autor: Jianrong L. Low, Anneta Naidoo, Gladys Yeo, Adam J. Gehring, Zi Zong Ho, Yin Hoe Yau, Susana G. Shochat, David M. Kranz, Antonio

Fuente: http://plos.srce.hr/



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