McCarthy Corinna, Shepherd Dawn, Fleire Sebastian, Stronge Victoria S, Koch Michael, Illarionov Petr A, Bossi Giovanna, Salio Mariolina, Denkberg Galit, Reddington Faye, Tarlton Andrea, Reddy B Gopal, Schmidt Richard R, Reiter Yoram, Griffiths Gillian M, van der Merwe P Anton, Besra Gurdyal S, Jones E Yvonne, Batista Facundo D, Cerundolo Vincenzo
Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
J Exp Med. 2007 May 14;204(5):1131-44. doi: 10.1084/jem.20062342. Epub 2007 May 7.
CD1d-restricted lymphocytes recognize a broad lipid range. However, how CD1d-restricted lymphocytes translate T cell receptor (TCR) recognition of lipids with similar group heads into distinct biological responses remains unclear. Using a soluble invariant NKT (iNKT) TCR and a newly engineered antibody specific for alpha-galactosylceramide (alpha-GalCer)-human CD1d (hCD1d) complexes, we measured the affinity of binding of iNKT TCR to hCD1d molecules loaded with a panel of alpha-GalCer analogues and assessed the rate of dissociation of alpha-GalCer and alpha-GalCer analogues from hCD1d molecules. We extended this analysis by studying iNKT cell synapse formation and iNKT cell activation by the same panel of alpha-GalCer analogues. Our results indicate the unique role of the lipid chain occupying the hCD1d F' channel in modulating TCR binding affinity to hCD1d-lipid complexes, the formation of stable immunological synapse, and cell activation. These data are consistent with previously described conformational changes between empty and loaded hCD1d molecules (Koch, M., V.S. Stronge, D. Shepherd, S.D. Gadola, B. Mathew, G. Ritter, A.R. Fersht, G.S. Besra, R.R. Schmidt, E.Y. Jones, and V. Cerundolo. 2005. Nat. Immunol 6:819-826), suggesting that incomplete occupation of the hCD1d F' channel results in conformational differences at the TCR recognition surface. This indirect effect provides a general mechanism by which lipid-specific lymphocytes are capable of recognizing both the group head and the length of lipid antigens, ensuring greater specificity of antigen recognition.
CD1d限制性淋巴细胞可识别多种脂质。然而，CD1d限制性淋巴细胞如何将对具有相似基团头部的脂质的T细胞受体（TCR）识别转化为不同的生物学反应仍不清楚。我们使用可溶性不变自然杀伤T细胞（iNKT）TCR和一种新设计的针对α-半乳糖神经酰胺（α-GalCer）-人CD1d（hCD1d）复合物的特异性抗体，测量了iNKT TCR与负载一组α-GalCer类似物的hCD1d分子的结合亲和力，并评估了α-GalCer和α-GalCer类似物从hCD1d分子上的解离速率。我们通过研究同一组α-GalCer类似物诱导的iNKT细胞突触形成和iNKT细胞活化来扩展这一分析。我们的结果表明，占据hCD1d F'通道的脂质链在调节TCR与hCD1d-脂质复合物的结合亲和力、稳定免疫突触的形成以及细胞活化方面具有独特作用。这些数据与先前描述的空载和负载hCD1d分子之间的构象变化一致（Koch, M., V.S. Stronge, D. Shepherd, S.D. Gadola, B. Mathew, G. Ritter, A.R. Fersht, G.S. Besra, R.R. Schmidt, E.Y. Jones, and V. Cerundolo. 2005. Nat. Immunol 6:819-826），表明hCD1d F'通道的不完全占据导致TCR识别表面的构象差异。这种间接效应提供了一种通用机制，通过该机制脂质特异性淋巴细胞能够识别脂质抗原的基团头部和长度，从而确保抗原识别具有更高的特异性。
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