Disparate Thermodynamics Governing T Cell Receptor-MHC-I Interactions Implicate Extrinsic Factors in Guiding MHC Restriction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 17; pp. 6641 - 6646
• Main Authors: Ely, Lauren K., Beddoe, Travis, Clements, Craig S., Matthews, Jacqueline M., Purcell, Anthony W., Kjer-Nielsen, Lars, McCluskey, James, Rossjohn, Jamie
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.04.2006
• Subjects: Amino Acid Sequence; beta 2-Microglobulin - chemistry; beta 2-Microglobulin - metabolism; Binding Sites; Biochemistry; Biological Sciences; Entropy; Epstein-Barr Virus Nuclear Antigens - genetics; Epstein-Barr Virus Nuclear Antigens - metabolism; HLA-B Antigens - chemistry; HLA-B Antigens - metabolism; HLA-B8 Antigen; Humans; Hydrogen bonds; Hydrophobic and Hydrophilic Interactions; Immunity; Immunology; In Vitro Techniques; Ligands; Ligation; Medical research; Models, Molecular; Molecular interactions; Molecules; Multiprotein Complexes; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide Fragments - metabolism; Protein Conformation; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Signal Transduction; Surface areas; Surface Plasmon Resonance; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; Thermodynamics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0600743103

The underlying basis of major histocompatibility complex (MHC) restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide-MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC restriction than appreciated previously.