Activation of invariant NKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-gamma production and dampening of the adaptive Th1 and Th17 responses.
Activation of invariant NKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-gamma production and dampening of the adaptive Th1 and Th17 responses.
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DOI：
10.4049/jimmunol.181.7.4791
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发表时间：
2008-10-01
期刊：
影响因子：
--
通讯作者：
Caspi RR
中科院分区：
文献类型：
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作者：
Grajewski RS;Hansen AM;Agarwal RK;Kronenberg M;Sidobre S;Su SB;Silver PB;Tsuji M;Franck RW;Lawton AP;Chan CC;Caspi RR
据报道，不变自然杀伤T细胞(iNKT细胞)不仅在先天免疫中发挥作用，而且还调节多种自身免疫模式。此外，iNKT细胞是产生与眼睛相关的免疫调节现象-前房相关免疫偏离(ACAID)的原型所必需的。在这里，我们使用实验性自身免疫性葡萄膜炎(EAU)的模型探索iNKT细胞在调节视网膜自身免疫中的作用，该模型用视网膜抗原(Ag)的葡萄膜原性方案IRBP免疫的小鼠。INKT数量的自然菌株特异性变异或iNKT的诱导遗传缺陷并不改变EAU的基线易感性。然而，iNKT功能似乎与易感性和体内的药理增强有关，在葡萄膜原性免疫时使用iNKT TCR配体可重复性改善疾病评分。不同的iNKT TCR配体的使用显示了对诱导的细胞因子谱的依赖性。令人惊讶的是，与配体α-C-GalCer(干扰素-γ和IL-4)和Och(主要是IL-4)相比，α-C-GalCer对EAU具有更好的保护作用，它诱导iNKT细胞产生强大的干扰素-γ，但只产生微弱的IL-4。α-C-Gal-Cer的保护作用与降低适应性抗原特异性干扰素-γ和IL-17的产生有关，并被全身中和干扰素-γ所抵消。这些数据表明，药物激活iNKT细胞至少部分地通过涉及先天产生干扰素-γ以及随后抑制Th1和Th17效应反应的机制来保护EAU。
Invariant Natural Killer T cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). Here we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal antigen (Ag), IRBP. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with α-C-GalCer, which induces a strong IFN-γ but only a weak IL-4 production by iNKT cells, in contrast to the ligands α-GalCer (both IFN-γ and IL-4) and OCH (primarily IL-4). The protective effect of α-C-Gal-Cer was associated with a reduction of adaptive Ag specific IFN-γ and IL-17 production and was negated by systemic neutralization of IFN-γ. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-γ and a consequent dampening of the Th1 as well as the Th17 effector responses.