T cell positive selection by a high density, low affinity ligand.
Interaction of the alpha beta T cell receptor (TCR) with major histocompatibility (MHC) molecules occupied with any of a large collection of peptides derived from self proteins is a critical step in driving T cell "positive" selection in the thymus. Interaction with this same pool of self-peptide/MHC ligands deletes T cells with potential self-reactivity. To examine how T cells survive both of these processes to form a self-tolerant mature repertoire, mice were constructed whose entire class II MHC IEk specific repertoire was positively selected on a single peptide covalently attached to the IEk molecule. In these mice T cells were identified that could respond to a variant of the positively selecting peptide bound to IEk. The affinities of the TCRs from these T cells for the positively selecting ligand were extremely low and at least 10-fold less than those for the activating ligand. These results support the theory that positive selection is driven by TCR affinities lower than those involved in T cell deletion or activation and that, if present at high concentration, even very low affinity ligands can positively select.
Liu
C P
CP
Howard Hughes Medical Institute, Division of Basic Immunology, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Crawford
F
F
Marrack
P
P
Kappler
J
J
D000595:Amino Acid Sequence; D001216:Asparagine; D001483:Base Sequence; D017635:Clonal Anergy; D003062:Codon; D003545:Cysteine; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D006825:Hybridomas; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000737:chemistry / Q000276:immunology*; D015183:Restriction Mapping; D013601:T-Lymphocytes / Q000276:immunology*
D003062:Codon; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D007376:Interleukin-2; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D001216:Asparagine; D003545:Cysteine