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TCR-ligand k(off) rate correlates with the protective capacity of antigen-specific CD8(+) T cells for adoptive transfer

Item Type:Article
Title:TCR-ligand k(off) rate correlates with the protective capacity of antigen-specific CD8(+) T cells for adoptive transfer
Creators Name:Nauerth, M. and Weissbrich, B. and Knall, R. and Franz, T. and Dössinger, G. and Bet, J. and Paszkiewicz, P.J. and Pfeifer, L. and Bunse, M. and Uckert, W. and Holtappels, R. and Gillert-Marien, D. and Neuenhahn, M. and Krackhardt, A. and Reddehase, M.J. and Riddell, S.R. and Busch, D.H.
Abstract:Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. T cells within a certain range of high avidity for their cognate ligand are believed to be most effective. T cell receptor (TCR) transfer experiments indicate that a major part of avidity is hardwired within the structure of the TCR. Unfortunately, rapid measurement of structural avidity of TCRs is difficult on living T cells. We developed a technology where dissociation (koff rate) of truly monomeric peptide-major histocompatibility complex (pMHC) molecules bound to surface-expressed TCRs can be monitored by real-time microscopy in a highly reliable manner. A first evaluation of this method on distinct human cytomegalovirus (CMV)-specific T cell populations revealed unexpected differences in the koff rates. CMV-specific T cells are currently being evaluated in clinical trials for efficacy in adoptive immunotherapy; therefore, determination of koff rates could guide selection of the most effective donor cells. Indeed, in two different murine infection models, we demonstrate that T cell populations with lower koff rates confer significantly better protection than populations with fast koff rates. These data indicate that koff rate measurements can improve the predictability of adoptive immunotherapy and provide diagnostic information on the in vivo quality of T cells.
Keywords:Adoptive Immunotherapy, Adoptive Transfer, CD8-Positive T-Lymphocytes, Cultured Cells, MHC Class I Genes, T-Cell Antigen Receptors, Animals, Mice
Source:Science Translational Medicine
Publisher:American Association for the Advancement of Science
Page Range:192ra87
Date:3 July 2013
Official Publication:https://doi.org/10.1126/scitranslmed.3005958
PubMed:View item in PubMed

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