Crossreactive T Cells Spotlight the Germline Rules for αβ T Cell-Receptor Interactions with MHC Molecules

Abstract

To test whether highly crossreactive alphabeta T cell receptors (TCRs) produced during limited negative selection best illustrate evolutionarily conserved interactions between TCR and major histocompatibility complex (MHC) molecules, we solved the structures of three TCRs bound to the same MHC II peptide (IAb-3K). The TCRs had similar affinities for IAb-3K but varied from noncrossreactive to extremely crossreactive with other peptides and MHCs. Crossreactivity correlated with a shrinking, increasingly hydrophobic TCR-ligand interface, involving fewer TCR amino acids. A few CDR1 and CDR2 amino acids dominated the most crossreactive TCR interface with MHC, including Vbeta8 48Y and 54E and Valpha4 29Y, arranged to impose the familiar diagonal orientation of TCR on MHC. These interactions contribute to MHC binding by other TCRs using related V regions, but not usually so dominantly. These data show that crossreactive TCRs can spotlight the evolutionarily conserved features of TCR-MHC interactions and that these interactions impose the diagonal docking of TCRs on MHC.

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

“…The germline-encoded V genes of the TCR are thought to determine bias toward the MHC (4,5), and consistent with this view there is evidence for preserved "interaction motifs" between the Vgene encoded regions of a TCR and a given MHC-II allotype (6,7). This has only been reported within a narrow slice of the Vβ repertoire, where consensus Vβ8.2 + CDR2β-mediated interactions were observed with closely related pMHC-II molecules (6,7).…”

“…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 "interaction codon" hypothesis is that the CDR1 and CDR2 loops contact the MHC, whereas the CDR3 loops "read-out" the peptide leading to an inherent MHC bias of TCR recognition.…”

“…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)(4)(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.…”

Structural immunology and crystallography help immunologists see the immune system in action: How T and NK cells touch their ligands

“…Recent study focusing on the interaction of one particular Vb segment (Vb8.2) with different I-A MHC alleles has demonstrated the conservation of specific TCR-MHC interfacial contacts (12,13). A ''codon hypothesis'' which suggests that each TCR variable-region gene product engages each type of MHC through a ''menu'' of structurally coded recognition motifs that have arisen through coevolution has been proposed to clarify the existence of ''TCR-MHC bias'' or ''germlineencoded recognition'' of MHC.…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…Significant changes in TCR CDR3 loops can take place upon binding (57)(58)(59) and CDR3 can occupy different conformations depending upon which ligand is bound (60,61 mechanisms produced occur simul-taneously in the interface, not limited to molecular mimicry and CDR loop shifts (62). Recently, it has been reported that the cross-reactivity correlated with a shrinking, increasingly hydrophobic TCR-ligand interface (63), and a few conserved amino acids in CDR1 and CDR2 were involved in the engagement (63,64).…”