Structural and kinetic basis for low affinity cross-reactivity in T cell allorecognition.
The alloreactive BM3.3TCR interacts with high affinity with H-2Kb loaded with the endogenous peptide pBM1 (INFDFNTI), and shows low affinity cross-reactivity for H-2Kb loaded with a viral peptide VSV8 (RGYVYQGL), CTL activity requiring 10(3)-fold higher peptide concentration and being highly sensitive to inhibition by anti-CD8 monoclonal antibody. VSV8 peptides substituted with pBM1/TCR contact residues (N6 and T7) retained low affinity characteristics and among pBM1 peptides substituted with residues Q6 and/or G7 present in VSV8, only pBM1(G7) was recognized, albeit with characteristics akin to those of VSV8. Despite the difference in KD values and the faster dissociation rate of multimeric VSV8/H-2Kb as compared to pBM1/H-2Kb complexes, similar TCR occupancy could be achieved with both multimers either at 4 or 37 degrees C. Only TCR engagement with pBM1/H-2Kb, however, resulted in early (Ca2+ flux) and late (CD69 expression) activation events in naive BM3.3TCR CD8 T cells. CD8 coreceptor, essential for binding of the weak agonists, was dispensable for binding of pBM1/H-2Kb multimers and their induction of signaling in naive T cells. Hence, high number of TCR and coreceptor engagement by weak agonists fail to substitute for strong agonist TCR engagement that can be coreceptor-independent and involve a limited number of TCR.
Guimezanes
Annick
A
Centre d'Immunologie de Marseille-Luminy, CNRS-INSERM-Univ. Méditerranée, Marseille, France. guimezanes@ciml.univ-mrs.fr
Montero-Julian
Félix
F
Schmitt-Verhulst
Anne-Marie
AM
D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D020013:Calcium Signaling / Q000502:physiology; D003429:Cross Reactions / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology*; D007700:Kinetics; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D016827:CD8 Antigens; D006649:Histocompatibility Antigens