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

真菌是免疫应答受损的宿主中的机会致病菌。宿主通过感知微生物并激活先天性和获得性免疫来消除感染的微生物。在此过程中，TLR和C型凝集素样受体发挥重要作用，天然免疫淋巴细胞如NKT细胞和γδ T细胞被激活，本研究旨在阐明TLR 2和dectin-1（β-glucan receptor）在树突状细胞（DC）识别马尔尼菲青霉菌（Penicillium marneffei）中的作用。我们还发现，dectin-1的作用不同的真菌，如其有限的作用，感应白色念珠菌和新型隐球菌。此外，我们还发现C. albicans、假丝酵母C.新型曲霉、烟曲霉和丝孢酵母属（Trichosporon spp.）C.通过诱导IL-12的产生和CD 40的表达激活DC，并且这些活性在C.白色念珠菌和C.新人类来自这些真菌的DNA进入内体区室并与TLR 9相互作用。这种机制可能在体内发挥作用，因为肺部感染了某种C。在其他研究中，为了阐明NKT细胞介导的宿主防御C.在新生隐球菌感染的实验中，我们试图在该真菌病原体的裂解物中发现NKT细胞识别的可能的糖脂抗原，并显示骨髓来源的DC与C.新生儿通过诱导IFN-γ的产生激活含有大量NKT细胞的肝单个核细胞（LMNC），而抗CD 1d单抗、CD 1d KO小鼠DC和Jα 18 KO小鼠LMNC均能强烈抑制IFN-γ的产生。这些结果有力地支持了C.激活NKT细胞的新生儿。

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.