Interplay between T cell receptor binding kinetics and the level of cognate peptide presented by major histocompatibility complexes governs CD8+ T cell responsiveness.

Details

Serval ID
serval:BIB_82B9FE6D3127
Type
Article: article from journal or magazin.
Collection
Publications
Title
Interplay between T cell receptor binding kinetics and the level of cognate peptide presented by major histocompatibility complexes governs CD8+ T cell responsiveness.
Journal
Journal of Biological Chemistry
Author(s)
Irving M., Zoete V., Hebeisen M., Schmid D., Baumgartner P., Guillaume P., Romero P., Speiser D., Luescher I., Rufer N., Michielin O.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
287
Number
27
Pages
23068-23078
Language
english
Abstract
Through a rational design approach, we generated a panel of HLA-A*0201/NY-ESO-1(157-165)-specific T cell receptors (TCR) with increasing affinities of up to 150-fold from the wild-type TCR. Using these TCR variants which extend just beyond the natural affinity range, along with an extreme supraphysiologic one having 1400-fold enhanced affinity, and a low-binding one, we sought to determine the effect of TCR binding properties along with cognate peptide concentration on CD8(+) T cell responsiveness. Major histocompatibility complexes (MHC) expressed on the surface of various antigen presenting cells were peptide-pulsed and used to stimulate human CD8(+) T cells expressing the different TCR via lentiviral transduction. At intermediate peptide concentration we measured maximum cytokine/chemokine secretion, cytotoxicity, and Ca(2+) flux for CD8(+) T cells expressing TCR within a dissociation constant (K(D)) range of ∼1-5 μM. Under these same conditions there was a gradual attenuation in activity for supraphysiologic affinity TCR with K(D) < ∼1 μM, irrespective of CD8 co-engagement and of half-life (t(1/2) = ln 2/k(off)) values. With increased peptide concentration, however, the activity levels of CD8(+) T cells expressing supraphysiologic affinity TCR were gradually restored. Together our data support the productive hit rate model of T cell activation arguing that it is not the absolute number of TCR/pMHC complexes formed at equilibrium, but rather their productive turnover, that controls levels of biological activity. Our findings have important implications for various immunotherapies under development such as adoptive cell transfer of TCR-engineered CD8(+) T cells, as well as for peptide vaccination strategies.
Keywords
Adaptive Immunity/immunology, Apoptosis/immunology, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Calcium/metabolism, Chemokines/metabolism, Chemokines/secretion, Cytokines/metabolism, Cytokines/secretion, HEK293 Cells, Humans, Immunotherapy, Active/methods, Lymphocyte Activation/immunology, Major Histocompatibility Complex/immunology, Models, Immunological, Neoplasms/immunology, Peptide Fragments/immunology, Peptide Fragments/metabolism, Protein Binding/immunology, Receptors, Antigen, T-Cell/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
11/06/2012 14:30
Last modification date
20/08/2019 15:42
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