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], Sjgren'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.
SHORT NARRATIVE Consistent with emerging evidence that Interferons (IFNs) play a far more pervasive role in regulating immune response than first imagined, the largest family of IFNs (i.e., type I) consists of 17 members, all encoded in a single locus. Intriguingly, genetic studies have determined that at least half of these IFN genes are under strong evolutionary selective pressure; raising the question as what functionally distinct roles they serve. To explore this important question, we propose to generate mice in which the corresponding murine IFN type I locus has either been deleted in its entirety or such that only a single IFN gene is retained.