CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance
Tomohiro Koga, … , José C. Crispín, George C. Tsokos
Tomohiro Koga, … , José C. Crispín, George C. Tsokos
Published March 25, 2014
Citation Information: J Clin Invest. 2014;124(5):2234-2245. https://doi.org/10.1172/JCI73411.
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Research Article Immunology

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

Abstract

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.

Authors

Tomohiro Koga, Christian M. Hedrich, Masayuki Mizui, Nobuya Yoshida, Kotaro Otomo, Linda A. Lieberman, Thomas Rauen, José C. Crispín, George C. Tsokos

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Figure 9

Model depicting the molecular mechanisms whereby CaMK4 controls the expression of IL-17.

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Model depicting the molecular mechanisms whereby CaMK4 controls the expr...
Engagement of the TCR causes an increase in intracellular calcium that leads to the activation of CaMK4. Active CaMK4 translocates to the nucleus, in which it phosphorylates CREM-α, which can bind to Il17 promoter. On the other hand, active CaMK4 also phosphorylates AKT, resulting in the activation of the AKT/mTOR/S6K pathway. S6K interacts with RORγ and enhances its nuclear translocation, leading to transcriptional control of IL-17.