Distinct subsets of human invariant NKT cells differentially regulate T helper responses via dendritic cells
Distinct subsets of human invariant NKT cells differentially regulate T helper responses via dendritic cells
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DOI：
10.1002/eji.200737838
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发表时间：
2008-04-01
影响因子：
5.4
通讯作者：
Matsushita, Sho
中科院分区：
文献类型：
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作者：
Liu, Tian-Yi;Uemura, Yasushi;Matsushita, Sho
不变的自然杀伤T（iNKT）细胞调节辅助性T（Th）1/2平衡并引起免疫应答的增强或抑制。然而，iNKT细胞发挥这些对比功能的确切机制仍然难以捉摸。我们在此证明，人iNKT细胞的两个主要不同亚群，CD 4（+）CD 8 β（-）（CD 4（+））和CD 4（-）CD 8 β（-）（双阴性; DN）细胞，表达功能性CD 40配体（CD 40 L），但它们通过相互的NKT-DC相互作用差异地调节树突状细胞（DC）功能，从而影响随后的Th应答。由α-半乳糖神经酰胺（α-GalCer）负载的DC刺激的CD 4亚群立即产生大量的IL-4和IL-13，其与IFN-γ一起增强DC的CD 40 L诱导的IL-12产生。相反，DN亚群通过细胞溶解消除DC，并将活DC改变为默认亚型，进而显著下调IL-12水平。因此，由CD 4亚群刺激的DC优先诱导Th 1应答，而与DN亚群反应的DC诱导向Th 2应答的转变。这些发现可能为更好地理解iNKT-DC串扰控制Th 1/2平衡的贡献以及iNKT细胞在各种疾病中的不同影响提供重要见解。
Invariant natural killer T (iNKT) cells regulate the T helper (Th) 1/2 balance and elicit either enhancement or suppression of the immune responses. However, the exact mechanism by which iNKT cells exert these contrasting functions has remained elusive. We demonstrate herein that two major distinct subsets of human iNKT cells, CD4(+)CD8 beta(-) (CD4(+)) and CD4(-)CD8 beta(-) (double negative; DN) cells, express functional CD40 ligand (CD40L), but they differentially regulate the dendritic cell (DC) function by reciprocal NKT-DC interactions, thereby influencing the subsequent Th response. The CD4 subset stimulated by alpha-galactosylceramide (alpha-GalCer)-loaded DC immediately produced massive amounts of IL-4 and IL-13, which together with IFN-gamma-enhanced CD40L-induced IL-12 production by DC. In contrast, the DN subset eliminated the DC by cytolysis and changed the living DC into a default subtype, in turn markedly down-regulating the levels of IL-12. Therefore, the DC stimulated by the CD4 subset preferentially induced Th1 responses, whereas the DC reacted with the DN subset induced a shift toward Th2 responses. These findings may provide an important insight into better understanding the contribution of iNKT-DC crosstalk governing the Th1/2 balance and the diverse influences of iNKT cells in various diseases.