Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
J Immunol. 2010 Jan 1;184(1):141-53. doi: 10.4049/jimmunol.0902880. Epub 2009 Nov 30.
Certain glycolipid Ags for Valpha14i NKT cells can direct the overall cytokine balance of the immune response. Th2-biasing OCH has a lower TCR avidity than the most potent agonist known, alpha-galactosylceramide. Although the CD1d-exposed portions of OCH and alpha-galactosylceramide are identical, structural analysis indicates that there are subtle CD1d conformational differences due to differences in the buried lipid portion of these two Ags, likely accounting for the difference in antigenic potency. Th1-biasing C-glycoside/CD1d has even weaker TCR interactions than OCH/CD1d. Despite this, C-glycoside caused a greater downstream activation of NK cells to produce IFN-gamma, accounting for its promotion of Th1 responses. We found that this difference correlated with the finding that C-glycoside/CD1d complexes survive much longer in vivo. Therefore, we suggest that the pharmacokinetic properties of glycolipids are a major determinant of cytokine skewing, suggesting a pathway for designing therapeutic glycolipids for modulating invariant NKT cell responses.
某些糖脂抗原可引导 Valpha14i NKT 细胞的整体细胞因子平衡。与已知最有效的激动剂α-半乳糖神经酰胺相比，具有 Th2 偏向性的 OCH 具有较低的 TCR 亲和力。尽管 OCH 和α-半乳糖神经酰胺暴露于 CD1d 的部分相同，但结构分析表明，由于这两种抗原埋藏脂质部分的差异，存在细微的 CD1d 构象差异，这可能解释了抗原效力的差异。具有 Th1 偏向性的 C-糖苷/CD1d 与 OCH/CD1d 的 TCR 相互作用更弱。尽管如此，C-糖苷仍能引起 NK 细胞更强烈地下游激活以产生 IFN-γ，这解释了它促进 Th1 反应的原因。我们发现，这种差异与 C-糖苷/CD1d 复合物在体内存活时间更长的发现相关。因此，我们建议糖脂的药代动力学特性是细胞因子偏向的主要决定因素，这为设计用于调节不变 NKT 细胞反应的治疗性糖脂提供了一种途径。
