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

真菌感染中NKT细胞和γδT细胞激活先天免疫反应及其调节

• 批准号: 18590413
• 负责人: KAWAKAMI Kazuyoshi
• 金额: $ 2.55万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590413/
• 关键词: fungus; Cryptococcus neoformans; Candida albicans; Penicillium marneffei; innate immunity; NKT cells; DNA; TLR9; 真菌感染; γδT細胞; 樹状細胞; CDId; 脂質抗原; IFN一γ

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.

真菌是免疫应答受损的宿主中的机会致病菌。宿主通过感知感染的微生物并激活先天性和获得性免疫来消除它们。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.白色念珠菌、C.新型酵母、烟曲霉和毛孢子菌属。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.白色念珠菌和念珠菌。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。

项目成果

自然免疫リンパ球による真菌感染防御の協調的制御

先天免疫淋巴细胞协调控制真菌感染防御

• 发表时间: 2006
• 期刊: 日本真菌学会雑誌 47
• 作者: 金城武士;藤田次郎;川上和義
• 通讯作者: 川上和義

Co-operative regulation of anti-fungal host host defense by innate immune lymphocytes

先天免疫淋巴细胞协同调节抗真菌宿主防御

• 发表时间: 2006
• 期刊: Japanese Journal of Medical Mycology 47
• 作者: Kinjo T;Fujita J;Kawakami K,
• 通讯作者: Kawakami K,

Role of interferon in host defense to bacterial and fungal infection

干扰素在宿主防御细菌和真菌感染中的作用

• 发表时间: 2007
• 期刊: Inflammation and Immunity 15
• 作者: Hatta M;Kaku M;Kawakami K,
• 通讯作者: Kawakami K,

Role of interferon-gamma in Valphal4+ natural killer T cell-mediated host defense against Streptococcus pneumonia in infection in murine lungs

干扰素-γ 在 Valphal4 自然杀伤 T 细胞介导的宿主防御肺炎链球菌感染小鼠肺部中的作用

• 发表时间: 2007
• 期刊: Microbes and Infection 9
• 作者: Nakamatsu M;et. al.
• 通讯作者: et. al.

NKT細胞及びγσT細胞に依存した肺感染病態制御機構の追求

寻求依赖 NKT 细胞和 γσT 细胞控制肺部感染病理状况的机制

• 发表时间: 2006
• 期刊: 炎症と免疫 14
• 作者: 金城武士;藤田次郎;川上和義;川上和義
• 通讯作者: 川上和義