Type I Interferons are important contributors in autoimmunity. In multiple sclerosis (MS), an autoimmune disease affecting the central nervous system, recombinant interferon-beta (IFN-β) has been shown to reduce relapse rate, disability progression, and formation of new brain and spinal cord lesions in patients with relapsing-remitting (RRMS) disease. However, little is known about its mechanism of action with regard to disease outcome, and 25% of RRMS patients are IFN-β non-responders. Interferon regulatory factor-7 (IRF-7) is a major transcriptional regulator that coordinates the production of endogenous IFN-β, and is also regulated by type I interferons.  In a mouse model of MS, IRF-7-deficient (IRF7KO) mice develop more severe disease than wild type controls (p<0.0001), and central nervous system (CNS) type-I IFN responses are significantly blunted in the IRF7KO hosts.  Moreover, cellular infiltration and levels of various Th17-associated cytokines, including IL-1α, IL-1β, IL-6, IL-17, and GM-CSF, as well as Th17-associated chemokines including, CXCL1 and CXCL2, are higher in the spinal cords of IRF7KO compared to WT mice.  Using an adoptive transfer mouse model of MS where IRF7KO or WT T cells were polarized under Th1 or Th17 conditions prior to transfer, we find that Th17-polarized IRF7KO T cells are more pathogenic than their WT counterparts (p=0.03), whereas Th1-polarized IRF7KO T cells were less pathogenic than similarly-treated WT cells (p<0.0001).  Taken together, our data suggest that IRF-7, and by extension IFN-β, controls the generation of disease-associated Th17 T cells as one mechanism of suppressing disease.  We have collected patient samples in our Holtom-Garrett Multiple Sclerosis Research Center, and will use these to determine whether IFN-β non-responsiveness correlates with a Th1, opposed to a Th17, driven disease.