Type I
interferons (IFNs) are an important family of cytokines which enable the immune
system to fight viral and bacterial infections. These cytokines are unique since multiple subtypes
signal through the same
heterodimeric receptor composed of high (IFNAR2) and low (IFNAR1) affinity
components. Conventionally, formation of the IFN signaling complex is thought
to be initiated by IFN binding to IFNAR2 with the subsequent recruitment of IFNAR1.
IFNα subtypes and IFNβ, the main IFNs produced in response to viral and
bacterial infections, elicit different biological effects despite utilising a
common receptor. To date we have limited understanding of the mechanism for
this. We have used biophysical techniques to characterise the IFNβ:IFNAR1 interaction,
and expression profiling and a genetically-modified mouse model of sepsis to demonstrate
the consequences of the IFNβ/IFNAR1 interaction in vivo. We demonstrate that a different functional capability of
IFNβ is dictated by its ability to interact directly with IFNAR1, independently
of IFNAR2. We thus report that IFNβ
in complex with IFNAR1 shows unique interaction interfaces than previously
defined for other type I IFN complexes. We also demonstrate that this IFNβ:IFNAR1
complex occurs in vivo and participates
in transduction of signals in mice. Using microarray analysis we have
identified a novel IFNβ signaling axis that occurs independently of IFNAR2 and
that induces the expression of genes encoding chemokines, cytokines and other previously
unknown interferon stimulated genes. Using
a mouse model of sepsis we also show that the unique mode of IFNAR1 engagement
by IFNβ contributes to lethality in this disease model. Our results reveal for
the first time the unique mechanism of IFNAR receptor engagement by IFNβ which
may explain the unique functional attributes that IFNβ possesses and may lead
to therapeutic interventions for the treatment of sepsis and other diseases
involving IFNβ.