Tissue inflammation in several autoimmune diseases, including SLE and MS, has 
been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; 
however, the factors that promote Th17-driven autoimmunity are unclear. Here, we 
present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) 
is increased and required during Th17 cell differentiation. Isolation of naive T 
cells from a murine model of lupus revealed increased levels of CaMK4 following 
stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 
induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce 
IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of 
IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine 
models. Inhibition of CaMK4 reduced Il17 transcription through decreased 
activation of the cAMP response element modulator α (CREM-α) and reduced 
activation of the AKT/mTOR pathway, which is known to enhance Th17 
differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE 
and healthy individuals inhibited Th17 differentiation through reduction of 
IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition 
has potential as a therapeutic strategy for Th17-driven autoimmune diseases.