RESUMEN

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.

Asunto(s)

Antígenos CD1/metabolismo , Regiones Determinantes de Complementariedad/metabolismo , Epítopos de Linfocito T/metabolismo , Ácidos Micólicos/inmunología , Ácidos Micólicos/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Secuencia de Aminoácidos , Presentación de Antígeno/genética , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos Bacterianos/química , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Antígenos CD1/química , Arginina/genética , Línea Celular , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/genética , Epítopos de Linfocito T/química , Epítopos de Linfocito T/genética , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T/genética , Humanos , Células Jurkat , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo , Ácidos Micólicos/química , Receptores de Antígenos de Linfocitos T alfa-beta/química , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Transfección