title: T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC.
abstract: T-cell activation results from productive T-cell receptor (TCR) engagement by a cognate peptide-MHC (pMHC) complex on the antigen presenting cell (APC) surface, a process leading to the polarization of the T-cell secretory machinery toward the APC interface. We have previously shown that the half-life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters determining T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate the efficiency of T-cell secretory machinery polarization toward an APC still remains unclear. Here, by using altered peptide ligands conferring different half-lives to the TCR/pMHC interaction, we have tested how this parameter can control T-cell polarization. We observed that only TCR/pMHC interactions with intermediate half-lives can promote the assembly of synapses that lead to T-cell activation. Strikingly, intermediate half-life interactions can be competed out by short half-life interactions, which can efficiently promote T-cell polarization and antagonize T-cell activation that was induced by activating intermediate half-life interactions. However, short TCR/pMHC interactions fail at promoting phosphorylation of signaling molecules at the T-cell-APC contact interface, which are needed for T-cell activation. Our data suggest that although intermediate half-life pMHC ligands promote assembly of activating synapses, this process can be inhibited by short half-life antagonistic pMHC ligands, which promote the assembly of non activating synapses.
authors.affiliation: Millennium Nucleus on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
authors.forename: Leandro J
authors.initials: LJ
authors.lastname: Carreño
authors.forename: Erick M
authors.initials: EM
authors.lastname: Riquelme
authors.forename: Pablo A
authors.initials: PA
authors.lastname: González
authors.forename: Nicolas
authors.initials: N
authors.lastname: Espagnolle
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Riedel
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valitutti
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D016764:Cell Polarity; D006056:Golgi Apparatus / Q000648:ultrastructure; D054992:Immunological Synapses / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D008024:Ligands; D010455:Peptides