Abstract
T cell discrimination of self and non-self is predicated on αβ T cell receptor (TCR) co-recognition of peptides presented by MHC molecules. Over the past 20 years, structurally focused investigations into this MHC-restricted response have provided profound insights into T cell function. Simultaneously, two models of TCR recognition have emerged, centred on whether the TCR has, through evolution, acquired an intrinsic germline-encoded capacity for MHC recognition or whether MHC reactivity is conferred by developmental selection of TCRs. Here, we review the structural and functional data that pertain to these theories of TCR recognition, which indicate that it will be necessary to assimilate features of both models to fully account for the molecular drivers of this evolutionarily ancient interaction between the TCR and MHC molecules.
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Acknowledgements
The authors thank P. Zareie for helpful comments and contributions. This work was supported by funding from the Australian National Health and Medical Research Council (NHMRC) and the Australian Research Council (ARC). N.L.L.G. is an ARC Future Fellow, S.G. is a Monash Senior Research Fellow and J.R. is an Australian ARC Laureate Fellow.
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Nature Reviews Immunology thanks B. Baker, C. Garcia and P. Marrack for their contribution to the peer review of this work.
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Supplementary information
41577_2018_7_MOESM1_ESM.pdf
Supplementary Figure 1 Cumulative number of TCR–pMHC ternary complex crystal structures and antigen-specific TCR sequences.
Glossary
- Register
-
The position of a peptide within the binding groove of the MHC molecule.
- MHC allomorphs
-
Different forms of an MHC protein encoded by different MHC alleles.
- TCR bias
-
Preferential usage of T cell receptors (TCRs) with specific characteristics, including gene segment usage and/or complementarity-determining region 3 (CDR3) sequence, that is typically observed in antigen-specific TCR repertoires.
- Degeneracy
-
The ability of a T cell receptor to recognize more than one peptide–MHC complex.
- Ternary complexes
-
Protein complexes containing three different molecules bound together — namely, the T cell receptor, peptide and an MHC molecule.
- Pairwise interactions
-
Conserved interactions between particular residues on the MHC molecule with paired or matching residues on the T cell receptor.
- Molecular mimicry
-
Similarity in peptide sequences that is sufficient to induce cross reactivity among T cell receptors.
- Expression quantitative trait locus
-
A genetic locus that contributes to variation in expression levels of particular genes.
- Public sequences
-
T cell receptor sequences that are often found across multiple individuals.
- Proximate causation
-
The immediate influences on an outcome, for example, thymic selection of T cell receptors that can recognize MHC molecules.
- Ultimate causation
-
The distal or evolutionary influences on an outcome, for example, the evolution of germline-encoded T cell receptor recognition of MHC molecules.
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La Gruta, N.L., Gras, S., Daley, S.R. et al. Understanding the drivers of MHC restriction of T cell receptors. Nat Rev Immunol 18, 467–478 (2018). https://doi.org/10.1038/s41577-018-0007-5
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DOI: https://doi.org/10.1038/s41577-018-0007-5
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