Type I interferons (IFNs) are an important family of cytokines which enable the immune system to fight viral infections and cancer, and modulate the immune response. Type I IFNs are unique amongst cytokines since multiple ligands can signal through the same heterodimeric receptor composed of low (IFNAR1) and high (IFNAR2) affinity components. Despite sharing a receptor, discernible differences result from receptor engagement by different IFN subtypes. We recently demonstrated a molecular basis for the unique functional characteristics exhibited by IFNβ; it can bind and signal via IFNAR1 in the absence of IFNAR2, inducing a novel signaling axis that contributes to lethality in a mouse model of sepsis. Having determined the crystal structure of IFNβ bound to full length extracellular domain (ECD) of IFNAR1, we are validating the interface to identify key residues mediating this interaction, and further characterising the signaling pathway. The novel signaling axis we identified by microarray analysis of induced ISGs after in vivo IFNβ treatment of IFNAR2^-/-mice includes genes encoding proteins with known roles in sepsis. We now demonstrate that this treatment also induces phosphorylation of AKT in cells of the peritoneal cavity. Furthermore, we observed reduced levels of  B220+CD11c- leukocytes in the peritoneal cavity and increased presentation of TREM1 on the surface of Gr1+ peritoneal cells in an IFNAR1-IFNβ dependent manner. That TREM1 is known to amplify the lethal response associated with sepsis gives some mechanistic insight into how the IFNAR1-IFNβ signaling axis may be contributing to lethality in this disease. Our results further demonstrate the importance of IFNβ and IFNAR1 in the transmission of signals and in influencing cell numbers and increased surface expression of inflammatory mediators. Understanding how to abrogate IFNβ binding to IFNAR1, and the down stream effects of the IFNAR1-IFNβ signaling axis may aid in development of targeted therapeutics in IFNβ-mediated inflammation.