title: TCR-ligand koff rate correlates with the protective capacity of antigen-specific CD8+ T cells for adoptive transfer.
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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Nauerth
authors.forename: Bianca
authors.initials: B
authors.lastname: Weißbrich
authors.forename: Robert
authors.initials: R
authors.lastname: Knall
authors.forename: Tobias
authors.initials: T
authors.lastname: Franz
authors.forename: Georg
authors.initials: G
authors.lastname: Dössinger
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bet
authors.forename: Paulina J
authors.initials: PJ
authors.lastname: Paszkiewicz
authors.forename: Lukas
authors.initials: L
authors.lastname: Pfeifer
authors.forename: Mario
authors.initials: M
authors.lastname: Bunse
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.forename: Rafaela
authors.initials: R
authors.lastname: Holtappels
authors.forename: Dorothea
authors.initials: D
authors.lastname: Gillert-Marien
authors.forename: Michael
authors.initials: M
authors.lastname: Neuenhahn
authors.forename: Angela
authors.initials: A
authors.lastname: Krackhardt
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005805:Genes, MHC Class I / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell