The widely accepted kinetic proofreading theory proposes that rapid TCR dissociation from a peptide/MHC ligand allows for stimulation of early but not late T cell activation events, explaining why low-affinity TCR ligands are poor agonists. We identified a low-affinity TCR ligand which stimulated late T cell responses but, contrary to predictions from kinetic proofreading, inefficiently induced early activation events. Furthermore, responses induced by this ligand were kinetically delayed compared to its high-affinity counterpart. Using peptide/MHC tetramers, we showed that activation characteristics could be dissociated from TCR occupancy by the peptide/MHC ligands. Our data argue that T cell responses are triggered by a cumulative signal which is reached at different time points for different TCR ligands.
Bibliographical noteFunding Information:
We thank Kris Hogquist, Marc Jenkins, and Dan Mueller for critical review of the manuscript and Traci Zell and the Jameson and Hogquist labs for practical and intellectual contributions. This work was supported by the A.C.S. (RPG 99-264-01 TO S.C.J.) and the NIH (AI38903 to S.C.J. and GM39476 to N.R.J.G.). C.R. was supported by a postdoctoral fellowship from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation (DRG 1465), M.A.D. was supported by an NIH Immunology Training grant (T32 AI-07313), and S.M.A. is a Special Fellow of the Leukemia and Lymphoma Society. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche Ltd.