6533b85dfe1ef96bd12be7e8

RESEARCH PRODUCT

TCR-Ligand koff rate correlates with the protective capacity of antigen-specific CD8+ T cells for adoptive transfer.

subject

description

Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. Thereby, 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 hard-wired 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.