Croudace Joanne E, Curbishley Stuart M, Mura Manuela, Willcox Carrie R, Illarionov Petr A, Besra Gurdyal S, Adams David H, Lammas David A
MRC Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, UK.
BMC Immunol. 2008 Dec 3;9:71. doi: 10.1186/1471-2172-9-71.
Human CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as alpha-galactosylceramide (alphaGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with alphaGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon.
Although all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population.
(i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to alphaGalCer.
人类CD1d限制性不变自然杀伤T细胞（iNKT）是一类独特的T淋巴细胞，可识别糖脂抗原，如α-半乳糖神经酰胺（αGalCer），并在T细胞受体（TCR）激活后产生Th1和Th2细胞因子。iNKT细胞在体外与αGalCer和白细胞介素2（IL-2）一起培养时，以CD1d限制性方式扩增。然而，人类iNKT细胞的扩增率在个体之间存在差异，这对治疗性操纵该途径的尝试具有影响。我们研究了一组25名健康人类供体，以评估他们体外iNKT细胞对CD1d配体刺激的扩增反应的变异性，并研究了一些可能影响这一现象的因素。
尽管所有供体的循环iNKT细胞数量相当，但它们在体外对一系列CD1d配体和IL-2刺激14天的生长速率高度依赖于供体。观察到两种可重复的iNKT扩增供体反应模式，我们将其称为“强”或“弱”iNKT反应者。供体反应表型与年龄、性别、循环iNKT频率或所使用的CD1d配体无关。向“弱”反应者供体培养物中添加外源性重组人白细胞介素4（IL-4）可显著提高其iNKT增殖能力，但未达到与“强”反应者供体相当的水平。然而，在“强”反应者供体中，向其培养物中添加IL-4并未显著改变扩增的CD3+群体中iNKT细胞的频率。
（i）人类iNKT细胞对CD1d配体激活的体外扩增高度依赖于供体，（ii）观察到两种可重复的供体iNKT扩增模式，可分为“强”和“弱”反应者表型，（iii）供体iNKT反应表型与年龄、性别、循环iNKT细胞频率或所使用的CD1d配体无关，（iv）向“弱”而非“强”反应者供体培养物中添加IL-4可显著增加其体外iNKT细胞对αGalCer的扩增。
