Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

Abstract

αβ T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementaritydetermining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.MHC restriction | T cell recognition | structural immunology | immunogenetics D uring thymic selection αβ T cell receptors (TCRs) are selected for weak reactivity with one or more self-peptides in complex with self-MHC (major histocompatibility complex), resulting in mature T cells being restricted to recognize processed peptides only when they are presented by self-MHC molecules (1). The exquisite specificity of TCR-pMHC binding must address the highly polymorphic nature of the MHC and variable peptide cargo. The antigen-recognition site of the TCR is made up of six complementarity-determining regions (CDRs), three each from the α and β chains (2). Currently, it is postulated that the CDR1 and 2 loops underpin the specificity or "bias" toward the MHC, whereas the CDR3 loops recognize the diverse range of bound peptides (3-5). Recent studies support the view that the T cell repertoire is intrinsically biased toward the MHC through contacts mediated by conserved TCR Vα and Vβ residues (6). However, the factors governing MHC restriction, a central paradigm of antigen-specific T cell immunity, remain unclear.Presumably as a consequence of the polymorphic pMHC landscape, and the inherent diversity of the responding T cell repertoire, structural studies have shown that the TCR engages the pMHC-I and pMHC-II surfaces in a range of different docking modes (2). Nevertheless, conserved pairwise interactions between closely related Vβ8.2 + TCRs and pMHC-II molecules were identified, leading to the concept that there are defined interaction "motifs" or "codons" between the Vα and/or Vβ domains of a TCR and a given MHC allotype (3,(6)(7)(8). Central to the "int...

Preemptive priming readily overcomes structure-based mechanisms of virus escape

“…Both the central position of the 155 "gate-keeper" residue in the MHCI binding cleft and its involvement in TCR ligation makes it a perfect target for viral escape (25,31). The present analysis established that H155 residue is important for pMHCI stability.…”

“…The large secondary response observed following challenge with a serologically different influenza virus incorporating the homologous mutation indicates that, despite what may be a suboptimal pMHCI conformation, the D b NPM6I and D b NPM6T epitopes can be recognized in way that is independent of any "typical" H155 presentation (25). The naïve D b NPM6T-specific precursor frequency detected by pMHCI tetramer binding is significantly smaller than that detected for the other mutant D b NPM6X epitopes.…”

“…The structural changes for H155 and P7E induced by P6I generated a more featureless pMHCI surface. Because residue 155 of MHC is important for TCR-mediated interactions, these alterations can potentially influence TCR binding (24,25).…”

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

“…For example, changes to a peptide alone are sufficient to alter how the same TCR sits over the same MHC protein, altering TCR-MHC atomic contacts (13,14). Similar results are seen with changes to TCR variable domains or hypervariable loops, or even MHC mutations (15)(16)(17)(18). Perhaps not surprisingly then, there are no germ-line-based TCR-MHC contacts that are fully conserved at the atomic level when structures with TCRs sharing the same variable domain are compared.…”

Evolving concepts of specificity in immune reactions

“…CDR1 and CDR2 mostly contact MHC helices that flank the epitope-binding groove. Usually, CDR3 makes the most contacts with the central amino acids of the epitope (98).…”