A TCRα framework–centered codon shapes a biased T cell repertoire through direct MHC and CDR3β interactions

CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

“…Recently, 'ensemble refinement' of crystal data with MD simulations has suggested conformational diversity in the microsecond range, but the conformational changes implicated here-in would be on the millisecond to minutes scale; in this regard, NMR of membrane-bound receptors may offer promise [50][51][52][53][54] Finally, a dynamics mechanism driven by H-bonding networks is consistent with the knowledge that different T-cell dose-response curves are found at the same TCR affinity for the same pMHC [40,[55][56][57][58]. Even if we assume similar TCR-affinity for the three 4OZ structures, it appears that somatic selection directly effects H-bonds implicated in V-domain dynamics (dV), and (indirectly) germline:germline contacts between CDR2 and the MHC -helices (d) [24,44,49,[59][60][61]. Stabilization of H-bonding via charge-relays is implicated for V-domains with verylow pitch angles, as specified by the twist-tilt-sway (viz., orientation) and highly-restricted dV.…”

“…Interest in these particular DQ structures is due to celiac disease, an autoimmune-like condition known to be mediated by predominant T-cell clonotypes against ingested wheat. Some 95% of celiac patients express HLA-DQ2.5 (DQA*05/DQB1*02), while the rest are either HLA-DQ8 (DQA*03/DQB1*03:02), or DQ2.2 (DQA*02:01/DQB1*02) [24]. For our purposes, the crystal structures of these nearly identical complexes facilitated isolating the chemistry associated with V-domain rotational probability/volumetric density (dV).…”

iReceptor: A platform for querying and analyzing antibody/B‐cell and T‐cell receptor repertoire data across federated repositories

“…One recent example is a study of celiac disease by Gunnarsen et al (21), showing how these data can be used to answer long-standing questions in autoimmunity. Celiac disease (CD) occurs primarily in individuals with particular alleles at the HLA loci, a set of genes that are often associated with infectious and autoimmune disease susceptibility.…”

A TRAV26‐1‐encoded recognition motif focuses the biased T cell response in celiac disease

“…We have previously identified a framework-resident recognition motif centered on Y40 TCRα encoded by TRAV26-1, which is crucial for the response to DQ2.5glia-α2 of the prototypic TCR 364 [2]. The co-crystal structure of the similar TCR S16 bound to peptide:MHC (pMHC) shows that not only Y40 TCRα , but also Y38 TCRα and H55 TCRα contact particular residues of the MHC β-chain as well as the canonical CDR3β loop [3].…”

“…To assess whether alternative TRAV germline segments can form a similar Y40 TCRα -centered recognition motif and substitute for TRAV26-1, we re-analyzed with an improved processing pipeline a TCR sequence data set [2] (Supporting Information Table S1) generated by single-cell paired αβ-chain sequencing of gliadin-specific CD4 + effector memory T cells sorted from CeD patients using a blend of four HLA-DQ2.5:gluten tetramers. We filtered out clones with the canonical CDR3β loop typical for DQ2.5-glia-α2-reactive TCRs and identified two private clonotypes using TRAV gene segments other than TRAV26-1.…”