Structural and dynamic control of T‐cell receptor specificity, cross‐reactivity, and binding mechanism

Abstract

Over the past two decades, structural biology has shown how T-cell receptors engage peptide/major histocompatibility complex (MHC) complexes and provided insight into the mechanisms underlying antigen specificity and cross-reactivity. Here we review and contextualize our contributions, which have emphasized the influence of structural changes and molecular flexibility. A repeated observation is the presence of conformational melding, in which the T-cell receptor (TCR), peptide, and in some cases, MHC protein cooperatively adjust in order for recognition to proceed. The structural changes reflect the intrinsic dynamics of the unligated proteins. Characterization of the dynamics of unligated TCR shows how binding loop motion can influence TCR cross-reactivity as well as specificity towards peptide and MHC. Examination of peptide dynamics indicates not only peptide-specific variation but also a peptide dependence to MHC flexibility. This latter point emphasizes that the TCR engages a composite peptide/MHC surface and that physically the receptor makes little distinction between the peptide and MHC. Much additional evidence for this can be found within the database of available structures, including our observations of a peptide dependence to the TCR binding mode and structural compensations for altered interatomic interactions, in which lost TCR-peptide interactions are replaced with TCR-MHC interactions. The lack of a hard-coded physical distinction between peptide and MHC has implications not only for specificity and cross-reactivity but also the mechanisms underlying MHC restriction as well as attempts to modulate and control TCR recognition.

Peptide Modulation of Class I Major Histocompatibility Complex Protein Molecular Flexibility and the Implications for Immune Recognition*

“…When considered alongside our previous findings with the Tax and Tel1p peptides (10), our results imply that there can be an "extension of antigenicity" from the peptide to the MHC and that distinctions commonly made between the two weaken at the atomic level (42). For example, patterns of similar TCR-MHC interatomic interactions in structures of TCRs sharing variable gene segments bound to the same MHC have been used to help argue that TCRs maintain an intrinsic affinity toward MHC proteins (43).…”

Peptide-dependent Conformational Fluctuation Determines the Stability of the Human Leukocyte Antigen Class I Complex

“…In contrast, thermodynamic analyses using differential scanning calorimetry, circular dichroism (14,15), infrared spectrometry (45), and hydrogen/deuterium exchange mass spectroscopy (46) have indicated that pHLAs are flexible in solution. These studies indicated that the overall flexibility of pHLAs differs depending on the bound peptides, suggesting the importance of the fluctuation of HLA on its function (47). However, they did not show how pHLAs are stabilized by the bound peptides.…”

Superimposed Epitopes Restricted by the Same HLA Molecule Drive Distinct HIV-Specific CD8+ T Cell Repertoires

“…It is not unusual to observe CTL reactivity toward peptides of 8-12 aa in length around an optimal epitope. This observation is thought to reflect the flexibility of TCR-MHC pairing to accommodate peptides close to the optimal one, such that the same CD8 + T cells are able to recognize these peptides (39)(40)(41). In the present study, we examined CD8 + T cell responses against two superimposed HIV nef epitopes (RW8 and RF10) restricted by HLA-A*24:02.…”