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TCR-pMHC: Envisioning the specialized dynamics of the target 5-component complex

Cellular & Molecular Immunology volume 19, pages 657–659 (2022)Cite this article

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The mechanosensor theory of TCR function holds the α/β component of the T-cell antigen receptor complex ultimately responsible for adaptive immunity [1,2,3]. T-cell motility is envisioned to provide a force necessary to slow TCR dynamics as it sits on the pMHC ligand of an antigen presenting cell [1], which theoretically allows the TCR to discriminate different pMHC structures, principally by the so-called catch bonds (mostly H-bonds) at the interfaces of the 5-component complex (i.e., TCRα/TCRβ/peptide/MHC-IIα (or, MHC-heavy-chain)/MHC-IIβ (or MHC-light-chain) [1,2,3,4]. Such bonds become stronger/become more numerous/are revealed/are relieved of inhibition by some mechanism that is not yet clear [5]. Importantly, the force does not allow this same TCR to bind to a nontarget pMHC any differently than binding with no force at all [1,2,3,4,5,6]. There is little evidence (yet) of any particular cellular suprastructure directing the force strictly to the TCR engaged with the target pMHC [5]. However, any force is a vector; vectors have magnitude and direction; [7] and yet, it is currently unclear what this direction may mean. Do TCR–pMHC complexes need to be in a particular orientation to be induced by this force? Experimental forces in model systems presumably model a net force, i.e., the sum of all the force vectors affecting a protein complex at the interface of (at least two) cells [1,2,3,4,5]. One could argue that a force is required in the thymus as well, but we are still left with the same problem: [8] simply put, a given T cell seems to exist to find a pMHC that can recapitulate something about its positive-selection ligand, viz., involving the somatically constructed, variable (V) domains binding to pMHC [8, 9].

Most recently (Murray, J. S., Mol. Immunol. 144: 138–151; April 2022), the geometry of the structures of n = 40 V domains in solved TCR:pHLA-DR and TCR:pHLA-DQ was analyzed in detail, and the findings suggested at least one possibility for this long-sought structural linkage to positive selection [10]. Because the method used fixed amino acid (a.a.) positions in each α-helix of a given MHC to define the spatial orientation for the central cysteine of the TCR V-domain disulfide, it allows comparison between different structures (even between HLA isotype/allotype). Easily defined spherical coordinates for each V domain facilitated the solution of triple integral equations―defining a simple volume element (dV), which is actually a slice of a flat-top cone [7]. Calculations then revealed a path (dθ) that any given CDR2 takes along the polymorphic MHC α-helix [7, 10]. The generic triple integral equation with defined trigonometry is:

$${\int} {\int} \int_{{v}} {dv} = \int_{0}^{\sin ^{ - 1} \cdot r{{{{{{{\mathrm{/}}}}}}}}p} {\int_{0}^{\pi \cdot r{{{{{{{\mathrm{/}}}}}}}}4} {\int_{0}^{z/\cos \phi } {\rho ^2\sin \phi \,d\rho \,d\theta \,d\phi } } }$$

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Acknowledgements

Thanks to E.H. Murray, M.D., for reading the manuscript prior to review.

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    Joseph S. Murray

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Murray, J.S. TCR-pMHC: Envisioning the specialized dynamics of the target 5-component complex. Cell Mol Immunol 19, 657–659 (2022). https://doi.org/10.1038/s41423-022-00856-3

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