Predicted complementarity determining regions of the T cell antigen receptor determine antigen specificity.

Abstract

The antigen receptor on T cells (TCR) has been predicted to have a structure similar to a membrane‐anchored form of an immunoglobulin F(ab) fragment. Virtually all of the conserved amino acids that are important for inter‐ and intramolecular interactions in the VH‐VL pair are also conserved in the TCR V alpha and V beta chains. A molecular model of the TCR has been constructed by homology and we have used the information from this, as well as the earlier structural predictions of others, to study the basis for specificity. Specifically, regions of a TCR cloned from an antigen‐specific T cell were stitched into the corresponding framework of a second TCR. Results indicate that the substitution of amino acid sequences corresponding to the complementarity determining regions (CDRs) of immunoglobulin can convey the specificity for antigen and major histocompatibility complex molecules. These data are consistent with a role, but not an exclusive role, for CDR3 in antigen peptide recognition.

Differential Roles of T Cell Receptor α and β Chains in Ligand Binding Among H-2Kd-restricted Cytolytic T Lymphocyte Clones Specific for a Photoreactive Plasmodium berghei Circumsporozoite Peptide Derivative

“…The binding of the K(ABA) side chain in a hydrophobic pocket, formed mainly by CDR3␣ and V␣ framework residues, which are more conserved than CDR residues (34,35), may explain why these TCR were preferentially labeled at the ␣ chain even though they lacked any apparent sequence consensus (Table II). The finding that a side chain of an MHC-bound peptide interacts with TCR V␣ framework residues is not in agreement with the current concept of TCRligand interactions, which postulates that such residues interact primarily with CDR3 loops (6).…”

“…Moreover, the high similarity between both labeled secondary Pro-C digest fragments very strongly suggests that the labeled site was contained in the sequence between Pro-32 and Pro-41 (e.g. segment [33][34][35][36][37][38][39][40][41]. This is consistent with the observed molecular mass and the finding that the same secondary Pro-C digest fragments were observed upon treatment of the minor, later eluting labeled primary V-8 or tryptic fragments (data not shown).…”

Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice

“…Linearized TCR ␣-and ␤-chain constructs were transfected into the mouse T cell clone D10.G4.1 as described (31). Briefly, D10 cells were harvested 14 to 28 days after stimulation with antigen-presenting cells and conalbumin (Sigma), washed and resuspended in PBS ϩ 10 mM MgCl 2 at 3.1 ϫ 10 6 cells per ml.…”

“…Stable transfectants expressing these two TCR were established in the mouse T cell clone D10.G4.1 (D10). D10 has been successfully used in previous studies for the functional expression of mouse TCR with full reconstitution of their reactivity to an appropriate MHC͞peptide complex (31,32). As a control, a stable transfectant of the MCC͞I-E k -reactive TCR 5C.C7 also was generated in D10 (32).…”

Frequent Contribution of T Cell Clonotypes with Public TCR Features to the Chronic Response Against a Dominant EBV-Derived Epitope: Application to Direct Detection of Their Molecular Imprint on the Human Peripheral T Cell Repertoire

“…Early models based upon the crystal structure of MHC and Ig molecules proposed that CDR1 and CDR2 primarily contact residues of the MHC ␣-helices, whereas CDR3 contact the antigenic peptide in the MHC groove (1,2). The key role of CDR3 in recognition of the antigenic peptide was then confirmed experimentally through several approaches, such as peptide immunization of single-chain TCR transgenic mice (3,4) and site-directed mutagenesis (5). More recently, crystallographic analyses of several TCR/MHC/ peptide complexes have revealed a conserved diagonal orientation of the TCR over the MHC/peptide complex and identified several contact points between, respectively, the N-terminal and C-terminal halves of the peptide and the CDR3 loops of the TCR ␣-chain and TCR ␤-chain (6 -8).…”