Beeson Group Research

Activation of T Cells by Antigenic Peptide

A mechanistic model, kinetic discrimination, that relates receptor-ligand lifetimes to cell signaling has been developed and applied to T-cell activation. We are using the model as a paradigm for the rational design of peptides and peptidomimetics that alter T-cell responses. These studies will not only further develop the mechanistic model but may also lead to the development of novel immunotherapeutic compounds. To test the model we are also developing novel methods to measure the kinetics of the reactions of peptide-MHC complexes with the T-cell receptor. For example, kinetics of T cells moving in a laminar flow over peptide-MHC ligands on a supported lipid bilayer are being used to estimate receptor-ligand kinetics. These kinetics are then related to the extent of signaling in T cells triggered by variant peptides. We have also intiated a new program to develop a more comprehensive library of peptide variants.

Kinetic Discrimination Model We've proposed that the ability of T cells to discriminate different ligands is determined by the TCR-ligand dissociation rate. Ligands that bind for a short time produce only partly activated receptor complexes (RP1) which inhibit T-cell signaling. Ligands that bind for longer times produce fully activated receptor complexes (RP2) which signal for T-cell activation. It is proposed that the final T-cell response is an integration of these two types of signals. This model has been used to explain the reactivity of altered peptides that are either antagonists or partial agonists.

 

Altered MBP 1-11 Peptides are Partial Agonists The MBP 1-11 peptide is an autoantigen involved in EAE, a murine model for multiple sclerosis. Substitution of the Gln-3 residue, a TCR contact, with Asn (3N) diminishes the ability of the peptide to stimulate T-cell proliferation (top). Substitution of the Ser-2 residue, an MHC contact, with Thr (2T) also diminishes the ability of the peptide to stimulate T-cell proliferation (top). When combined, these two mutations (2T-3N), profoundly diminishes the peptide activity. Molecular models suggested that the 2T substitution would alter the side-chain conformation of the 3N residue. Although the 2T-3N peptide does stimulate T-cell proliferation at high concentrations (top), at lower concentrations it blocks proliferation induced by the agonist 4A peptide. These partial agonist peptides have the ability to modulate T-cell responses and may be useful in the treatment of autoimmune diseases. In the top panel proliferation of a T-cell clone is measured by incorporation of tritiated-thymidine. In the bottom panel, antigen presenting cells were pre-pulsed with the A4 peptide and then added to T cells with altered peptide. Proliferation was measured as the incorporation of tritiated thymidine.

home