Bailey Jennifer C, Iyer Abhirami K, Renukaradhya Gourapura J, Lin Yinling, Nguyen Hoa, Brutkiewicz Randy R
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Immunology. 2014 Dec;143(4):679-91. doi: 10.1111/imm.12353.
CD1d-mediated lipid antigen presentation activates a subset of innate immune lymphocytes called invariant natural killer T (NKT) cells that, by virtue of their potent cytokine production, bridge the innate and adaptive immune systems. Transforming growth factor (TGF-β) is a known immune modulator that can activate the mitogen-activated protein kinase p38; we have previously shown that p38 is a negative regulator of CD1d-mediated antigen presentation. Several studies implicate a role for TGF-β in the activation of p38. Therefore, we hypothesized that TGF-β would impair antigen presentation by CD1d. Indeed, a dose-dependent decrease in CD1d-mediated antigen presentation and impairment of lipid antigen processing was observed in response to TGF-β treatment. However, it was found that this inhibition was not through p38 activation. Instead, Smads 2, 3 and 4, downstream elements of the TGF-β canonical signalling pathway, contributed to the observed effects. In marked contrast to that observed with CD1d, TGF-β was found to enhance MHC class II-mediated antigen presentation. Overall, these results suggest that the canonical TGF-β/Smad pathway negatively regulates an important arm of the host's innate immune responses - CD1d-mediated lipid antigen presentation to NKT cells.
CD1d介导的脂质抗原呈递可激活一类先天性免疫淋巴细胞，即不变自然杀伤T（NKT）细胞，这类细胞凭借其强大的细胞因子分泌能力，在先天性免疫系统和适应性免疫系统之间起到桥梁作用。转化生长因子（TGF-β）是一种已知的免疫调节剂，可激活丝裂原活化蛋白激酶p38；我们之前已经表明p38是CD1d介导的抗原呈递的负调节因子。多项研究表明TGF-β在p38的激活中发挥作用。因此，我们推测TGF-β会损害CD1d介导的抗原呈递。事实上，在TGF-β处理后，观察到CD1d介导的抗原呈递呈剂量依赖性降低，脂质抗原加工受损。然而，发现这种抑制作用并非通过p38激活。相反，TGF-β经典信号通路的下游元件Smad 2、3和4促成了观察到的效应。与CD1d的情况形成显著对比的是，发现TGF-β可增强MHC II类分子介导的抗原呈递。总体而言，这些结果表明，经典的TGF-β/Smad通路负向调节宿主先天性免疫反应的一个重要环节——CD1d介导的向NKT细胞呈递脂质抗原。
