γδ T cell receptors recognize the non-classical major histocompatibility complex (MHC) molecule T22 via conserved anchor residues in a MHC peptide-like fashion.
The molecular mechanisms by which γδ T cells recognize ligand remain a mystery. The non-classical MHC molecule T22 represents the best characterized ligand for murine γδ T cells, with a motif (W … EGYEL) present in the γδ T cell receptor complementary-determining region 3δ (CDR3δ) loop mediating γδ T cell recognition of this molecule. Produced through V(D)J recombination, this loop is quite diverse, with different numbers and chemical types of amino acids between Trp and EGYEL, which have unknown functional consequences for T22 recognition. We have investigated the biophysical and structural effects of CDR3δ loop diversity, revealing a range of affinities for T22 but a common thermodynamic pattern. Mutagenesis of these CDR3δ loops defines the key anchor residues involved in T22 recognition as W … EGYEL, similar to those found for the G8 CDR3δ loop, and demonstrates that spacer residues modulate but are not required for T22 recognition. Comparison of the location of these residues in the T22 interface reveals a striking similarity to peptide anchor residues in classically presented MHC peptides, with the key Trp residue of the CDR3δ motif completing the deficient peptide-binding groove of T22. This suggests that γδ T cell recognition of T22 utilizes the conserved ligand-presenting nature of the MHC fold.
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA.
Andrew
A
Sandstrom
Louise
L
Scharf
Gabrielle
G
McRae
Andrew J
AJ
Hawk
Stephen C
SC
Meredith
Erin J
EJ
Adams
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D019277:Entropy; D006680:HLA Antigens / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
D022801:Complementarity Determining Regions; D006680:HLA Antigens; D010455:Peptides; D016692:Receptors, Antigen, T-Cell, gamma-delta; C516580:T22 peptide