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Nauerth, M.* ; Weißbrich, B.* ; Knall, R.* ; Franz, T.* ; Dössinger, G.* ; Bet, J.* ; Paszkiewicz, P.J.* ; Pfeifer, L.* ; Bunse, M.* ; Uckert, W.* ; Holtappels, R.* ; Gillert-Marien, D.* ; Neuenhahn, M. ; Krackhardt, A.M. ; Reddehase, M.J.* ; Riddell, S.R.* ; Busch, D.H.

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

Sci. Transl. Med. 5:192ra87 (2013)
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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 (k(off) 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 k(off) 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 k(off) rates confer significantly better protection than populations with fast k(off) rates. These data indicate that k(off) rate measurements can improve the predictability of adoptive immunotherapy and provide diagnostic information on the in vivo quality of T cells.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Superior Antitumor-activity ; Gene-transfer ; High-avidity ; Selective Expansion ; Reactive Tcr ; Lymphocytes ; Cytomegalovirus ; Mhc ; Reconstitution ; Infection
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 5, Issue: 192, Pages: , Article Number: 192ra87 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Institute of Molecular Immunology (IMI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-520100-001
G-501790-003
PubMed ID 23825303
DOI 10.1126/scitranslmed.3005958
WOS ID WOS:000321257600008
Erfassungsdatum 2013-08-02
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