Grant Ethan P, Beckman Evan M, Behar Samuel M, Degano Massimo, Frederique Daphney, Besra Gurdyal S, Wilson Ian A, Porcelli Steven A, Furlong Stephen T, Brenner Michael B
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.
J Immunol. 2002 Apr 15;168(8):3933-40. doi: 10.4049/jimmunol.168.8.3933.
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.
αβ TCR能够识别由MHC分子呈递的肽段，或由CD1蛋白呈递的脂质及糖脂。尽管目前已清楚了解肽段/MHC识别的结构基础，但尚不清楚TCR如何与脂质等截然不同的分子相互作用。最近，我们证明αβ TCR赋予了对脂质抗原和CD1异构体限制的特异性，这表明TCR可能识别脂质/CD1复合物。我们推测脂质可能通过其疏水的烷基和酰基链与CD1结合，使亲水的糖、磷酸和其他极性官能团暴露出来，以便与TCR互补决定区（CDR）相互作用。为了验证该模型，我们对DN1 TCR β链CDR3区域中预测在TCR/CD1复合物模型中位于CD1b α螺旋之间突出的残基进行了突变。此外，我们测试了分枝菌酸的带负电荷和极性官能团对抗原识别的需求。我们的研究结果表明，TCR的CDR环形成了CD1限制性TCR的抗原识别结构域，并表明脂质抗原的亲水区可以形成由TCR识别的组合表位。
