Activation of innate immune responses and its regulation by NKT cells and γδT cells in fungal infection

真菌是免疫反应受损的宿主中的机会性病原体。宿主通过感知被感染的微生物并激活先天免疫和获得性免疫来清除它们。在这一过程中，TLR2和C型凝集素样受体发挥了重要作用，并激活了天然免疫淋巴细胞，如NKT细胞和γδT细胞。在本研究中，我们阐明了TLR2和DECIN-1(β-葡聚糖受体)在树突状细胞识别马尔尼菲青霉菌中的作用。我们还发现Dectin-1的作用在不同的真菌中是不同的，表现在它对白色念珠菌和新生隐球菌的感知作用有限。此外，我们还发现来自白色念珠菌、新生念珠菌、烟曲霉菌和毛孢子菌的DNA。在白色念珠菌和新生念珠菌中，这些活性是通过TLR9/MYD88/NF_κB依赖的信号通路来调节的。这些真菌的DNA被运输到内体隔室，并与TLR9相互作用。这一机制可能在体内发挥作用，因为在TLR9基因中断(KO)小鼠中，某株新生弧菌的肺部感染恶化了。在其他研究中，为了探讨NKT细胞介导的宿主防御新生弧菌感染的机制，我们试图在这种真菌病原体的裂解物中发现一种可能被NKT细胞识别的糖脂抗原，结果表明，新生弧菌冲击的骨髓来源的DC通过诱导干扰素-γ的产生来激活含有大量NKT细胞的肝脏单个核细胞，这种作用可被抗CD 1D单抗或CD1dKO小鼠DC或来自Jα18KO小鼠的LMNC所强烈抑制。这些结果有力地支持了新生葡萄球菌中存在激活NKT细胞的糖脂抗原。

Fungi are opportunistic pathogens in hosts with impaired immune responses. Host eliminates the infected microorganisms by sensing them and developing the activation of innate and acquired immunity. During these processes, TLR and C-type lectin-like receptors play important roles and innate immune lymphocytes such as NKT cells and γδ T cells are activated.In this study, we clarified the contribution of TLR2 and dectin-1, a (β-glucan receptor, in the recognition of Penicillium marneffei by dendritic cells (DC). We also found that the role of dectin-1 differed among fungi, as shown by its limited role in sensing Candida albicans and Cryptococcus neoformans. Furthermore, we found that DNA from C. albicans, C. neoformans, Aspergillus fumigates and Trichosporon spp. activated DC by inducing IL-12 production and CD40 expression and that these activities were mediated by a TLR9/MyD88/NF_κB-dependent signaling pathway in case of C. albicans and C. neoformans. DNA from these fungi trafficked into endosomal compartments and interacted with TLR9. This mechanism was likely to function in vivo because lung infection with a certain strain of C. neoformans was worsened in TLR9 gene-disrupted (KO) mice.In other study, to address the mechanism of NKT cell-mediated host defense against C. neoformans infection, we tried to found a possible glycolipid antigen recognized by NKT cells in the lysates of this fungal pathogen and showed that bone marrow-derived DC pulsed with C. neoformans activated liver mononuclear cells (LMNC) containing much NKT cells by inducing IFN-γ production, which was strongly inhibited by neutralizing anti-CD 1d mAb or when DC from CDldKO mice or LMNC from Jα18KO mice were used. These results strongly supported the existence of glycolipid antigens in C. neoformans which activate NKT cells.