title: T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell.
abstract: CD8(+) T cells recognize peptides of eight to nine amino acid residues long in the context of MHC class I molecules on the surface of antigen-presenting cells (APCs). This recognition event is highly sensitive, as evidenced by the fact that T cells can be activated by cognate peptide/MHC complex (pMHC) at extremely low densities (1-50 molecules). High sensitivity is particularly valuable for detection of antigens at low density, such as those derived from tumor cells and intracellular pathogens, which can down-modulate cognate pMHCs from the surface of APCs to evade recognition by the adaptive immune system. T cell activation is only triggered in response to interactions between the T cell receptor (TCR) and the pMHC ligand that reach a specific half-life threshold. However, interactions with excessively long half-lives result in impaired T cell activation. Thus, efficient T cell activation by pMHC on the surface of APCs requires an optimal dwell time of TCR-pMHC interaction. Here, we show that, although this is a requirement at low cognate pMHC density on the APC surface, at high epitope density there is no impairment of T cell activation by extended TCR-pMHC dwell times. This observation was predicted by mathematical simulations for T cell activation by pMHC at different densities and supported by experiments performed on APCs selected for varied expression of cognate pMHC. According to these results, effective T cell activation depends on a complex interplay between inherent TCR-pMHC binding kinetics and the epitope density on the APC.
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: González
authors.forename: Leandro J
authors.initials: LJ
authors.lastname: Carreño
authors.forename: Daniel
authors.initials: D
authors.lastname: Coombs
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Mora
authors.forename: Edith
authors.initials: E
authors.lastname: Palmieri
authors.forename: Byron
authors.initials: B
authors.lastname: Goldstein
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Nathenson
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D000938:Antigen-Presenting Cells / Q000378:metabolism*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005434:Flow Cytometry; D006183:H-2 Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000502:physiology*; D018448:Models, Immunological; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D011948:Receptors, Antigen, T-Cell