Regulation of vaccine-induced anti-fungal T17 cells

疫苗诱导的抗真菌 T17 细胞的调节

• 批准号: 8450924
• 负责人: Marcel Wuethrich
• 金额: $ 41.39万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450924
• 关键词: Achievement; Address; Adjuvant; Adoptive Transfer; Alveolar; Alveolar Macrophages; Antifungal Agents; Antigens; Attenuated; Attenuated Live Virus Vaccine; Attenuated Vaccines; Biological Assay; Blastomyces; Blastomyces dermatitidis; Bone Marrow; C Type Lectin Receptors; CD4 Positive T Lymphocytes; Cause of Death; Cell Differentiation process; Cells; Clinical Trials; Coccidioides; Coccidioidomycosis; Communicable Diseases; Data; Dendritic Cells; Development; Engineering; Experimental Models; Foundations; Fungal Vaccines; Genetic Engineering; Glycoproteins; Goals; Histoplasma capsulatum; Histoplasmosis; Human; Immune; Immune response; Immunity; In Vitro; Infection; Knockout Mice; Knowledge; Lead; Ligands; Link; Lung; Mannans; Mannose; Mediating; Microbe; Modeling; Molecular; Mus; Mycoses; North America; Pathway interactions; Pattern; Pneumonia; Polysaccharides; Prevalence; Public Health; Receptor Signaling; Recombinants; Recruitment Activity; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Staging; System; T cell response; T-Cell Receptor; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Transgenic Mice; United States; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccines; Work; Yeasts; base; dectin 1; design; fungus; immunogenicity; in vivo; innovation; insight; interest; killings; macrophage; mannose receptor; microbial; mouse dectin-2; neutrophil; novel; novel vaccines; pathogen; public health relevance; receptor; response; screening; vaccine development

DESCRIPTION (provided by applicant): Vaccines against infectious disease have been hailed as the greatest achievement in public health over the last century. Despite the growing prevalence of severe fungal infections, no vaccines against fungi are in clinical trials or commercially available. We have engineered a live attenuated vaccine that protects against infection with the primary fungal pathogen Blastomyces dermatitidis. We and others have shown that vaccine immunity to this and other fungal infections is mediated by a dominant T1-cell response. In preliminary data, we found that T17 cells also are induced by vaccination and confer resistance against B. dermatitidis as well as related dimorphic fungi Coccidioides posadasii and Histoplasma capsulatum. In contrast to the prevailing dogma, we observed that T1 cells, but not T17 cells, are dispensable in this vaccine resistance and that T17 cells are also sufficient for the resistance. Vaccine-induced T17 cells mediated protection by recruiting and activating neutrophils and alveolar macrophages to the alveolar space to augment fungal killing. In this application, we propose to decipher the cellular receptors and innate signaling pathways that induce naive antigen-specific T-cells to differentiate into protective anti-fungal T17 cells. We have created a novel Blastomyces TCR transgenic mouse, which represents a key innovation that will let us analyze the requirements for differentiation of naive anti-fungal T-cells. We hypothesize that receptor recognition of Blastomyces mannans by the FcR3-Syk-Card9 and the TLR-Myd88 signaling pathways are essential to induce T17 cells and vaccine immunity. We also posit that Myd88-induced T17 differentiation involves pathway crosstalk between TLRs and Card9, and that TLRs collaborate with the mannose receptor to induce T17 cell differentiation. We provide strong preliminary data to support our hypotheses. Using our new Blastomyces-specific TCR Tg mouse, we have established an in vitro screen with bone marrow derived dendritic cells from knockout mice and an in vivo adoptive transfer system to delineate the signaling adaptors, pathogen recognition receptors, and fungal ligands that induce differentiation of naive antigen-specific CD4+ T- cells into protective T17 cells. Our approach offers a powerful complimentary strategy that will investigate the host receptors and signaling pathways in Aims 1 and 2, and the fungal ligands in Aim 3. Our work will provide new insight into the fungal pathogen recognition receptors and downstream signaling pathways, as well as the pathogen-associated molecular patterns that induce T17 cell differentiation. This knowledge will provide the fundamental basis for developing and designing new vaccine strategies against fungi, and will catalyze the discovery of novel adjuvants useful in vaccines against fungi and microbes in general.

描述（由申请人提供）：针对传染病的疫苗被誉为上个世纪公共卫生领域最伟大的成就。尽管严重真菌感染的患病率不断上升，但还没有针对真菌的疫苗进入临床试验或商业化。我们设计了一种减毒活疫苗，可以防止主要真菌病原体皮炎芽生菌的感染。我们和其他人已经证明，针对这种真菌感染和其他真菌感染的疫苗免疫力是由占主导地位的 T1 细胞反应介导的。在初步数据中，我们发现 T17 细胞也可以通过疫苗接种诱导，并赋予对皮炎芽孢杆菌以及相关二形性真菌波萨达球孢子菌和荚膜组织胞浆菌的抗性。与流行的教条相反，我们观察到T1细胞而不是T17细胞在这种疫苗抗性中是可有可无的，并且T17细胞也足以产生抗性。疫苗诱导的 T17 细胞通过招募和激活中性粒细胞和肺泡巨噬细胞到肺泡空间来介导保护，以增强真菌杀伤力。 在此应用中，我们建议破译诱导幼稚抗原特异性 T 细胞分化为保护性抗真菌 T17 细胞的细胞受体和先天信号传导途径。我们创造了一种新型芽生菌 TCR 转基因小鼠，它代表了一项关键创新，使我们能够分析初始抗真菌 T 细胞的分化要求。我们假设 FcR3-Syk-Card9 和 TLR-Myd88 信号通路对芽生菌甘露聚糖的受体识别对于诱导 T17 细胞和疫苗免疫至关重要。我们还假设 Myd88 诱导的 T17 分化涉及 TLR 和 Card9 之间的通路串扰，并且 TLR 与甘露糖受体协作诱导 T17 细胞分化。我们提供强有力的初步数据来支持我们的假设。使用我们新的芽生菌特异性 TCR Tg 小鼠，我们建立了一种体外筛选方法，使用来自基因敲除小鼠的骨髓来源的树突状细胞和体内过继转移系统来描绘信号转接器、病原体识别受体和诱导分化的真菌配体。将初始抗原特异性 CD4+ T 细胞转化为保护性 T17 细胞。我们的方法提供了一个强大的补充策略，将研究目标 1 和 2 中的宿主受体和信号通路，以及目标 3 中的真菌配体。我们的工作将为真菌病原体识别受体和下游信号通路以及诱导 T17 细胞分化的病原体相关分子模式。这些知识将为开发和设计针对真菌的新疫苗策略提供基础基础，并将促进发现可用于针对真菌和微生物的疫苗的新型佐剂。