Genetic characterization of the murine type I Interferon locus

描述（由申请人提供）：除了具有强大的抗病毒活性外，I型干扰素（IFN-Is）在调节免疫稳态方面发挥的重要作用越来越得到认可，无论是在基础上还是在免疫挑战期间。有趣的是，最近的研究表明，微生物组可能在指导基础活性方面发挥重要作用，特别是包括造血干细胞（hsc）的调节，以及它们产生的几种谱系（例如DCs， NK细胞和CD8 t细胞）。IFN-Is在对病毒和细菌病原体的先天反应中也起着重要作用，因此它们指导过渡到有效的适应性反应。与此一致的是，IFN-Is最近被发现在几种自身免疫性疾病（如系统性狼疮红斑症[SLE]、格林综合征、牛皮癣和特应性）和肿瘤免疫监测中发挥重要作用。鉴于这些重要发现，人们对开发更特异的基于IFN-I的治疗方法来治疗自身免疫、癌症和操纵造血干细胞重新产生了兴趣。值得注意的是，在人类中，ifn - 1家族由17个精心策划的成员组成，其中至少有一半是高度保守的，这就提出了一个有趣的问题：它们是否具有独特的生物学功能。不幸的是，大小

DESCRIPTION (provided by applicant): In addition to their potent antiviral activity, type I Interferons (IFN-Is) are increasingly recognized for the important role they play in regulating immune homeostasis, both basally and during an immune challenge. Intriguingly, recent studies suggest the microbiome may play an important role in directing basal activity, which notably includes regulation of hematopoietic stem cells (HSCs), and several lineages they give rise to (e.g., DCs, NK cells & CD8 T-cells). IFN-Is also play an important role during the innate response to viral and bacterial pathogens, whereupon they direct the transition to an effective adaptive response. Consistent with this, IFN-Is have recently been found to play a prominent role in several autoimmune diseases (e.g., systemic lupus erythematosis [SLE], Sj¿gren's syndrome, psoriasis & atopy) and in tumor immunosurveillance. Reflecting these important discoveries have been renewed interest in developing more specific IFN-I based therapeutics to treat autoimmunity, cancer and to manipulate HSCs. Remarkably, in humans the IFN-I family consists of 17 well-curated members, at least half of which are highly conserved, raising the intriguing question of whether they serve distinct biological functions. Unfortunately, the size of the IFN-I locus has precluded the development of effective tools to explore this important question. To this end we have developed targeting vectors that will enable us to either delete the entire IFN-I locus (i.e., IFN-Ilocus-/- mice) or to generate mice in which only the IFN-¿ gene is retained (i.e., IFN-¿only mice). The latter mouse will help evaluate the prevailing notion that IFN-¿ directs the basal IFN-I response. Two aims are proposed to complete the development and analysis of these mice. These data will be vital for subsequent studies in which these two lines will be exploited to explore the role that individual IFN-Is play in vivo. Aim I. Exploit IF-Ilocus-/- and IFN-¿only mice to explore the role IFN-¿ plays in regulating basal immune homeostasis. This will include evaluation of HSC and NK cell compartments. Aim II. Exploit IFN-Ilocus-/- and IFN-¿ mice to explore the role IFN-¿ plays in directing both only robust innate and adaptive responses to specific microbes.