The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation.
The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation.
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DOI：
10.1084/jem.20062342
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发表时间：
2007-05-14
期刊：
影响因子：
--
通讯作者：
Cerundolo V
中科院分区：
文献类型：
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作者：
McCarthy C;Shepherd D;Fleire S;Stronge VS;Koch M;Illarionov PA;Bossi G;Salio M;Denkberg G;Reddington F;Tarlton A;Reddy BG;Schmidt RR;Reiter Y;Griffiths GM;van der Merwe PA;Besra GS;Jones EY;Batista FD;Cerundolo V
CD 1d限制性淋巴细胞识别广泛的脂质范围。然而，CD 1d限制性淋巴细胞如何将T细胞受体（TCR）对具有相似组头的脂质的识别转化为不同的生物学反应仍不清楚。使用可溶性不变NKT（iNKT）TCR和α-半乳糖神经酰胺（α-GalCer）-人CD 1d（hCD 1d）复合物的新工程抗体，我们测量了iNKT TCR与负载一组α-GalCer类似物的hCD 1d分子的结合亲和力，并评估了α-GalCer和α-GalCer类似物从hCD 1d分子上解离的速率。我们通过研究同一组α-GalCer类似物的iNKT细胞突触形成和iNKT细胞活化来扩展该分析。我们的研究结果表明占据hCD 1d F′通道的脂质链在调节TCR与hCD 1d-脂质复合物的结合亲和力、稳定的免疫突触的形成和细胞活化中具有独特的作用。这些数据与先前描述的空的和加载的hCD 1d分子之间的构象变化一致（Koch，M.，V.S. Stronge，D. Shepherd，S. D.加多拉，B。Mathew，G. Ritter，A.R. Fersht，G.S. Besra，R.R.施密特，E.Y. Jones和V. Cerundolo。2005. Nat.Immunol6：819-826），表明hCD 1d F′通道的不完全占据导致TCR识别表面的构象差异。这种间接作用提供了一种一般机制，通过这种机制，脂质特异性淋巴细胞能够识别脂质抗原的基团头和长度，确保抗原识别的更大特异性。
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 α-galactosylceramide (α-GalCer)–human CD1d (hCD1d) complexes, we measured the affinity of binding of iNKT TCR to hCD1d molecules loaded with a panel of α-GalCer analogues and assessed the rate of dissociation of α-GalCer and α-GalCer analogues from hCD1d molecules. We extended this analysis by studying iNKT cell synapse formation and iNKT cell activation by the same panel of α-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.
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DOI：
10.1093/protein/gzg087
发表时间：
2003-09-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
Boulter, JM;Glick, M;Jakobsen, BK
通讯作者：
Jakobsen, BK
影响因子：
4.4
作者：
Giabbai, B;Sidobre, SP;Degano, M
通讯作者：
Degano, M
影响因子：
30.5
作者：
Moody, DB;Briken, V;Porcelli, SA
通讯作者：
Porcelli, SA
影响因子：
15.3
作者：
Kjer-Nielsen, L;Borg, NA;McCluskey, J
通讯作者：
McCluskey, J
影响因子：
30.5
作者：
Kinjo, Yuki;Tupin, Emmanuel;Kronenberg, Mitchell
通讯作者：
Kronenberg, Mitchell