Tissue specific role of IFNalpha/beta and IFNgamma in innate immuniy to prio path

I型干扰素（IFNa蛋白和IFNp家族）和II型IFN（IFNy）发挥核心和必需的作用， 在促进针对多种病毒、细菌和寄生虫的先天免疫中的作用。IFNs 不仅诱导保护宿主细胞免受病原体感染细胞内在机制，而且激活 导致NK细胞、巨噬细胞、多形核细胞活化的多种细胞外源性机制 白细胞和T细胞破坏受感染的细胞。我们对干扰素生物学的了解主要来自于 对IFN-应答细胞与无应答细胞进行的体外实验和体内方法，其中 通过使用中和或阻断单克隆抗体在小鼠中全面消除IFN应答性 或通过破坏编码IFN种类本身或其各自受体的基因。 这些研究的生理相关性已经被发现的人类所证实， 在产生或响应各种形式的IFN方面存在明显缺陷。然而，由于受体 由于IFN α/β或IFN γ几乎在所有细胞上都有表达，我们对它们的细胞特异性功能仍然知之甚少 这些细胞因子在体内。由于IFN在先天免疫中起着如此关键的作用，因此获得更详细的 不仅需要了解它们对不同细胞群体的共同和独特作用， 如果我们希望有意识地刺激先天免疫，无论是免疫学上还是治疗上， 保护我们免受自然发生的（例如大流行病毒感染）或故意产生的（例如， 生物恐怖主义）感染。装备（1）广泛了解干扰素生物学，施赖伯实验室有 从过去28年进行的分子和遗传实验中获得的（2）一个全面的 Unanue实验室内关于单核细胞增生李斯特菌免疫生物学的知识 感染，和（3）特别广泛和深刻的理解病毒学的其他成员，这是 MRCE计划带来了这一应用，我们建议生产和研究小鼠在稳定的C57 BL/6 在特定细胞类型中缺乏对IFN α/β或IFN γ的反应性的遗传背景，以定义组织 IFN对感染优先病原体的具体作用。

Type I Interferons (the family of IFNa proteins and IFNp) and Type II IFN (IFNy) play central and essential roles in promoting innate immunity against a wide variety of viruses, bacteria and parasites. The IFNs induce not only cell-intrinsic mechanisms that protect host cells against pathogen infection but also activate a variety of cell-extrinsic mechanisms leading to activation of NK cells, macrophages, polymorphonuclear leukocytes and T cells that destroy infected cells. Our knowledge of IFN biology has stemmed largely from in vitro experiments performed on IFN-responsive versus unresponsive cells and in vivo approaches in which IFN responsiveness is globally ablated in mice through use of neutralizing or blocking monoclonal antibodies or through disruption of genes encoding either the IFN species themselves or their respective receptors. The physiologic relevance of these studies have been validated by the discovery of humans who have distinct defects in either producing or responding to the various forms of IFN. However, since the receptors for IFNa/p or IFNy are expressed on nearly all cells, we still know very little about the cell-specific functions of these cytokines in vivo. Since the IFNs play such a key role in innate immunity, obtaining a more detailed understanding of their common and unique effects on different cell populations is not only needed but essential if we wish to intentionally stimulate innate immunity, either prophylactically or therapeutically, to protect us against naturally-occurring (e.g. pandemic viral infections) or intentionally-produced (e.g., bioterrorism) infections. Armed with (1) an extensive understanding of IFN biology that the Schreiber lab has gained from molecular and genetic experiments conducted over the last 28 years (2) a comprehensive knowledge that exists within the Unanue laboratory about the immunobiology of Listeria monocytogenes infection, and (3) the particularly broad and deep understanding of virology that the other members of this MRCE program bring to this application, we propose to produce and study mice on a stabilized C57BL/6 genetic background that lack responsiveness to IFNa/p or IFNy in specific cell types to define the tissue specific actions of the IFNs to infection with priority pathogens.