Abstract
Successful immunity requires that a limited pool of αβ T-cell receptors (TCRs) provide cover for a vast number of potential foreign peptide antigens presented by ‘self’ major histocompatibility complex (pMHC) molecules. Structures of unligated and ligated MHC class-I-restricted TCRs with different ligands, supplemented with biophysical analyses, have revealed a number of important mechanisms that govern TCR mediated antigen recognition. HA1.7 TCR binding to the influenza hemagglutinin antigen (HA306–318) presented by HLA-DR1 or HLA-DR4 represents an ideal system for interrogating pMHC-II antigen recognition. Accordingly, we solved the structure of the unligated HA1.7 TCR and compared it to both complex structures. Despite a relatively rigid binding mode, HA1.7 T-cells could tolerate mutations in key contact residues within the peptide epitope. Thermodynamic analysis revealed that limited plasticity and extreme favorable entropy underpinned the ability of the HA1.7 T-cell clone to cross-react with HA306–318 presented by multiple MHC-II alleles.
Highlights
Successful immunity requires that a limited pool of ab T-cell receptors (TCRs) provide cover for a vast number of potential foreign peptide antigens presented by ‘self’ major histocompatibility complex molecules
In order to analyze the degree of conformational plasticity during binding of a degenerate TCR to MHC-II, we determined the structure of the HA1.7 TCR using diffraction data extending to 2.4A (Table 1)
A greater degree of movement was required by the HA1.7 TCR to associate with DR4-HA compared to DR1-HA, possibly explaining the difference in binding affinity between the two complexes[42]
Summary
Successful immunity requires that a limited pool of ab T-cell receptors (TCRs) provide cover for a vast number of potential foreign peptide antigens presented by ‘self’ major histocompatibility complex (pMHC) molecules. Thermodynamic analyses of these TCR-pMHC-I interactions showed that binding was generally characterized by unfavorable entropy (i.e. transition from a disordered to an ordered state) which was counteracted by favorable enthalpy (i.e. an exothermic reaction mediated by a net gain in electrostatic interactions)[5] These analyses suggested that conformational plasticity in the TCR CDR loops was energetically favored and played an important role in Tcell antigen recognition and crossreactivity[6,7,8]. The relationship of how these conformational changes to the TCR might have influenced the potential degeneracy of the responding T-cell was not investigated[15] To explore this question further, we examined TCR-pMHC-II binding degeneracy using the HA1.7 TCR that recognizes an influenza hemagglutinin derived epitope (HA306–318). These data provide important new information concerning the molecular rules that govern antigen recognition by MHC-II restricted T-cells
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