Fine specificity of TCR complementarity-determining region residues and lipid antigen hydrophilic moieties in the recognition of a CD1-lipid complex.
alphabeta TCR can recognize peptides presented by MHC molecules or lipids and glycolipids presented by CD1 proteins. Whereas the structural basis for peptide/MHC recognition is now clearly understood, it is not known how the TCR can interact with such disparate molecules as lipids. Recently, we demonstrated that the alphabeta TCR confers specificity for both the lipid Ag and CD1 isoform restriction, indicating that the TCR is likely to recognize a lipid/CD1 complex. We hypothesized that lipids may bind to CD1 via their hydrophobic alkyl and acyl chains, exposing the hydrophilic sugar, phosphate, and other polar functions for interaction with the TCR complementarity-determining regions (CDRs). To test this model, we mutated the residues in the CDR3 region of the DN1 TCR beta-chain that were predicted to project between the CD1b alpha helices in a model of the TCR/CD1 complex. In addition, we tested the requirement for the negatively charged and polar functions of mycolic acid for Ag recognition. Our findings indicate that the CDR loops of the TCR form the Ag recognition domain of CD1-restricted TCRs and suggest that the hydrophilic domains of a lipid Ag can form a combinatorial epitope recognized by the TCR.
Grant
Ethan P
EP
Lymphocyte Biology Section, Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Beckman
Evan M
EM
Behar
Samuel M
SM
Degano
Massimo
M
Frederique
Daphney
D
Besra
Gurdyal S
GS
Wilson
Ian A
IA
Porcelli
Steven A
SA
Furlong
Stephen T
ST
Brenner
Michael B
MB
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018949:Antigens, CD1 / Q000737:chemistry / Q000378:metabolism*; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D009171:Mycolic Acids / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000942:Antigens, Bacterial; D018949:Antigens, CD1; C419394:CD1b antigen; D022801:Complementarity Determining Regions; D018984:Epitopes, T-Lymphocyte; D009171:Mycolic Acids; D016693:Receptors, Antigen, T-Cell, alpha-beta; D001120:Arginine