Interplay between T Cell Receptor Binding Kinetics and the Level of Cognate Peptide Presented by Major Histocompatibility Complexes Governs CD8+ T Cell Responsiveness
| Autor: | Philippe Guillaume, Michael Hebeisen, Melita Irving, Daniel E. Speiser, Pedro Romero, Immanuel F. Luescher, Daphné Schmid, Nathalie Rufer, Petra Baumgartner, Vincent Zoete, Olivier Michielin |
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| Rok vydání: | 2012 |
| Předmět: |
T cell
Immunology Receptors Antigen T-Cell Apoptosis chemical and pharmacologic phenomena Adaptive Immunity CD8-Positive T-Lymphocytes Biology Lymphocyte Activation Major histocompatibility complex Biochemistry Major Histocompatibility Complex T cell receptor binding Neoplasms medicine Humans Cytotoxic T cell Antigen-presenting cell Molecular Biology T-cell receptor Models Immunological Immunotherapy Active Cell Biology biochemical phenomena metabolism and nutrition Molecular biology Peptide Fragments HEK293 Cells medicine.anatomical_structure Chemokine secretion biology.protein Cytokines Calcium Chemokines CD8 Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 287:23068-23078 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.357673 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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