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Understanding the drivers of MHC restriction of T cell receptors


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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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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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Nicole L. La Gruta or Jamie Rossjohn.

Supplementary information

Supplementary Figure 1 Cumulative number of TCR–pMHC ternary complex crystal structures and antigen-specific TCR sequences.

Supplementary Table 1 Chronological list of unique TCR–pMHC complexes



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.


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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Further reading

Fig. 1: Chronological view of technological developments and conceptual advances that have furthered our understanding of TCR recognition of peptide–MHC.
Fig. 2: Overview of TCR recognition of peptide–MHC class I and peptide–MHC class II.
Fig. 3: Conventional and reversed polarity TCR docking on MHC molecules.
Fig. 4: Dual causation of MHC restriction of TCRs.