The T-cell receptor is not hardwired to engage MHC ligands

Abstract

The bias of αβ T cells for MHC ligands has been proposed to be intrinsic to the T-cell receptor (TCR). Equally, the CD4 and CD8 coreceptors contribute to ligand restriction by colocalizing Lck with the TCR when MHC ligands are engaged. To determine the importance of intrinsic ligand bias, the germ-line TCR complementarity determining regions were extensively diversified in vivo. We show that engagement with MHC ligands during thymocyte selection and peripheral T-cell activation imposes remarkably little constraint over TCR structure. Such versatility is more consistent with an opportunist, rather than a predetermined, mode of interface formation. This hypothesis was experimentally confirmed by expressing a hybrid TCR containing TCR-γ chain germ-line complementarity determining regions, which engaged efficiently with MHC ligands. MHC restriction | TCRT cells expressing an αβ T-cell receptor (TCR) are MHCrestricted, recognizing self-and foreign peptide epitopes presented by MHC class I and II molecules during thymic development and peripheral activation, respectively. Two mechanisms are proposed to underlie this ligand bias. First, the CD8 and CD4 coreceptors have dual specificity for extracellular MHC and the intracellular proximal kinase Lck. Consequently, when MHC class I or II ligands are engaged, Lck is colocalized with the TCR/CD3 complex initiating signal transduction. The importance of this mechanism in disadvantaging non-MHC ligands is highlighted by the recovery of T-cell selection, where MHC and the coreceptors are both absent in comparison to the absence of MHC alone (1). In this setting, non-MHC ligands drive thymic positive selection and are recognized by peripheral T cells (2). The ability of αβ TCRs to recognize non-MHC ligands does not rule out an intrinsic bias of the TCR for MHC ligands. Indeed, evidence for such a hardwired bias is suggested by pairwise interactions between TCR-β germ-line complementarity determining regions 1 and 2 (CDR1/2) and the MHC α-helices observed in several structures (3-7). Recently, such recurrent interactions have been shown to be dependent on the partner TCR-α chain, which can impose distinct modes of TCR-β engagement, suggesting they may not drive MHC specificity (8). Although the relatively limited set of TCR/MHCpeptide structures reveals a semiconserved docking geometry, the angle of TCR engagement varies by more than 60°and the generally central docking position can shift toward the peptide aminoor carboxy-terminus (9). Likewise, conserved features of the MHC α-helices, including exposure of the polypeptide backbone and surface depressions, have been suggested to provide energetically favorable sites for CDR engagement (5). However, a crucial role for specific MHC residues in TCR docking has not emerged (10). The role of germ-line TCR structure in the bias to MHC ligands has thus been perplexing, especially given the structural variability of both components. To investigate this, we have applied a unique mutagenesis approach based on redirecting V(D)J recombina...

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

“…We expanded on this here by demonstrating that, in the structural database of TCRs that bind HLA-A2, not only are there no conserved TCR-MHC contacts, even those amino acids in TCR germ-line loops that are the least variable make different contacts or do not contact A2 at all. These results are consistent with findings that diversified TCRs can still bind MHC (35), and prompted us to search for a more fundamental basis for MHC bias based upon compatibility rather than simply contacts. Through a combination of sequence, structural, and biophysical analyses, we demonstrated that TCR germ-line loops are enriched in the means to complement a polymorphic hot-spot region on the α1-helix of the class I MHC protein HLA-A2, consisting of positively charged residues that are absent from most other HLA-A alleles, as well as those of HLA-B and HLA-C. Burial of these charges is required for TCRs to sample peptides effectively, and without the ability to complement them, their burial would be highly unfavorable due to the energetic cost of desolvation (26,27).…”

“…Only a single H 0 site in the TCR germ-line loops was identified, the histidine at position 29 in CDR1β, whose presence has been noted previously and is thought to be involved in loop organization (35). Five H 1 sites were identified, one each in CDR1α, CDR2α, and CDR1β, and two in CDR2β.…”

Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune Response

“…An extension to this TCR hard-wiring concept is the "interaction codon hypothesis" pertaining to TCR-pMHC interactions, which posits that conserved pairwise interaction motifs between the germline-encoded regions of the TCR and the MHC underpin this TCR-MHC co-evolution (Adams et al, 2016). In contrast to the germline model, the selection model argues that MHC restriction is not an intrinsic feature of TCRs but is conferred by selection events in the thymus (Holland et al, 2012;Van Laethem et al, 2013). Here we show that the two TRBV17 + TCRs, which are found within the naïve T cell repertoire in wild type mice, adopt a reversed TCR-pMHC-I docking topology.…”

Restricting nonclassical MHC genes coevolve with TRAV genes used by innate-like T cells in mammals

“…As for the TR, evolutionarily conserved features of the CDR1 and CDR2 of several TRBV genes have been proposed to enable a conserved docking mode of the TR onto the classical MH (23), although this remains controversial (24,25). For TRA, the analysis is complex because the number of TRAV genes may be very large, with multiple subgroups and wide variation across species (≈50 to >350 within mammals).…”