Multiple sclerosis (MS) is an autoimmune neurodegenerative disease in which both adaptive and innate immunity play a role. CD4+
T cells, believed to be early effector cells in the disease, migrate to the central nervous system (CNS), leading to demyelination, axonal loss, and neurological disability. The cells of the innate immune system are also involved both in the initiation and progression of MS by influencing the effector function of T cells 
. Both Th1 and Th17 cells are involved in the pathogenesis of MS, and are the primary effector cells in experimental autoimmune encephalomyelitis (EAE), the most common animal model of MS 
. These lineages have distinct effector functions and are characterized by the expression of specific transcription factors and cytokines. The differentiation of naïve CD4+
T cells to interferon-γ (IFN-γ)-producing T helper (Th1) cells is dependent on IFN-γ and interleukin (IL)-12, activation of STAT1 and STAT4, respectively, and the transcription factor Tbet 
. TGF-β and IL-6, and STAT3 drive IL-17-producing T helper (Th17) cell differentiation in a process that is dependent on the transcription factor ROR-γt 
. Although IL-23 is not needed for differentiation, it has an essential role in pathogenicity of Th17 cells perhaps by promoting expansion and stability 
The IFN-γ-STAT1 signaling axis has an important pleiotropic role, both pathogenic and protective, in autoimmune diseases including MS and its mouse model, EAE 
. Both Th1 and Th17 cells are independently capable of inducing autommunity in mouse models and they not only play a role in regulating one another, but that they have a more complex, both overlapping and differential, role in tissue inflammation 
. There is also increasing evidence of the plasticity/instability of the Th17 cell phenotype; Th17 cells may acquire Tbet expression, gaining the ability to secrete IFN-γ in addition to IL-17 
. These dual cytokine expressing Th17 cells may ultimately lose the ability to secrete IL-17 and convert into Th1-like cells. Thus the finding that Th17 cells can turn into Th1 cells highlights the importance of controlling the effector function of Th1 cells once disease is established.
We have recently found that relapsing-remitting MS segregates into a Th1 or a Th17 disease and that each form of disease is differentially responsive to type I IFN therapy 
. Thus the elucidation of signaling pathways regulating the production and expansion of specific Th effector cells in EAE and MS is a necessary goal to identify new specific targets for therapeutic intervention. A lot is known about the transcription factors and cytokines that are determinant for the differentiation of Th1 and Th17 effector cells, but the mechanisms regulating their production, expansion and pathogenic function in disease are still largely undefined.
GSK3 is a constitutively active serine/threonine kinase that is a critical modulator of innate and adaptive immunity through the regulation of several transcription factors important in the production of cytokines and inflammation, including NF-kB, CREB, AP-1 and STATs 
. We have previously shown that the GSK3 inhibitor lithium is prophylactic and therapeutic in EAE 
. Recovery from EAE in lithium treated mice was associated with reduced demyelination, reduced microglia activation, and reduced CD4+
T cell infiltration in the spinal cord. We also found that treatment of mice in vivo
with the GSK3 inhibitor lithium, inhibited myelin oligodendrocyte glycoprotein peptide (MOG35–55
)-specific T cell proliferation and significantly reduced MOG35–55
-specific production of IFN-γ, IL-6, and IL-17 from splenocytes 
. GSK3 has been shown to facilitate IFN-γ mediated activation of macrophages 
. Furthermore inhibition of GSK3 in macrophages suppresses activation of STAT3 and STAT5, and constrains the synergistic activation by IFN-γ and lipopolysaccharides (LPS) of STAT3 
. However the mechanism of the therapeutic action of lithium in neuroinflammation in vivo
is still unresolved. In this study we tested the hypothesis that lithium is beneficial in EAE through GSK3 regulation of IFN-γ signaling. Our results show that lithium suppresses Th1 but not Th17 neuroinflammation, and through inhibition of GSK3 tunes IFN-γ-STAT1 signaling for optimal therapeutic efficacy in EAE.