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The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide-MHC recognition

Nature Immunology volume 6, pages 171–180 (2005)Cite this article

Abstract

The energetic bases of T cell recognition are unclear. Here, we studied the 'energetic landscape' of peptide–major histocompatibility complex (pMHC) recognition by an immunodominant αβ T cell receptor (TCR). We quantified and evaluated the effect of natural and systematic substitutions in the complementarity-determining region (CDR) loops on ligand binding in the context of the structural detail of each component of the immunodominant TCR-pMHC complex. The CDR1 and CDR2 loops contributed minimal energy through direct recognition of the antigen and instead had a chief function in stabilizing the ligated CDR3 loops. The underlying energetic basis for recognition lay in the CDR3 loops. Therefore the energetic burden of the CDR loops in the TCR-pMHC interaction is variable among TCRs, reflecting the inherent adaptability of the TCR in ligating different ligands.

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Figure 1: Binding analysis of LC13 TCR Ala point mutants to FLR–HLA-B8 by surface plasmon resonance.
Figure 2: Effect of substitutions on the LC13–FLR–HLA-B8 interaction.
Figure 3: LC13 TCR residues that are essential for interaction with FLR–HLA-B8.
Figure 4: Natural variation in 'public' TCR sequences used in the HLA-B8-restricted, FLR-specific antiviral CD8+ T cell response.
Figure 5: The LC13 TCR and HLA-B8 hotspot.

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Acknowledgements

The authors thank F. Carbone and A. Brooks for critically reading the manuscript, and K. Davern (The Walter and Eliza Hall Institute of Medical Research) for assistance in producing the mAbs to LC13. Supported by a Wellcome Trust Senior Research Fellowship in Biomedical Science in Australia (J.R.), the University of Melbourne (A.W.P.), National Health and Medical Research Council (Australia) and Australian Research Council, the Roche Organ Transplantation Research Foundation and the Juvenile Diabetes Research Foundation.

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  1. Natalie A Borg and Lauren K Ely: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, Monash Centre for Synchrotron Science, School of Biomedical Sciences, Monash University, Clayton, 3800, Victoria, Australia

    Natalie A Borg, Lauren K Ely, Travis Beddoe, Whitney A Macdonald, Hugh H Reid, Craig S Clements & Jamie Rossjohn

  2. Department of Microbiology & Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Anthony W Purcell, Lars Kjer-Nielsen & James McCluskey

  3. Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia

    John J Miles & Scott R Burrows

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Supplementary information

Supplementary Fig. 1

Specificity of mAbs used to probe integrity of recombinant TCRs. (PDF 86 kb)

Supplementary Fig. 2

LC13 TCR and HLA-B8. (PDF 1514 kb)

Supplementary Fig. 3

Nucleotide and amino acid sequences of previously reported “public” TRBV7-8 chains(a) and TRAV26-2 chains(b) isolated from FLR-specifc CD8+ T cells (PDF 95 kb)

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Borg, N., Ely, L., Beddoe, T. et al. The CDR3 regions of an immunodominant T cell receptor dictate the 'energetic landscape' of peptide-MHC recognition. Nat Immunol 6, 171–180 (2005). https://doi.org/10.1038/ni1155

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