CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance
Tomohiro Koga, Christian M. Hedrich, Masayuki Mizui, Nobuya Yoshida, Kotaro Otomo, Linda A. Lieberman, Thomas Rauen, José C. Crispín, George C. Tsokos
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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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 2

CaMK4 controls the development of Th17 cells.

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CaMK4 controls the development of Th17 cells. (A) Naive T cells differen...
(A) Naive T cells differentiated for 72 hours in Th1, Th2, or Th17 conditions from spleens of B6 or B6.Camk4–/– mice were gated on TCRβ+CD4+ and stained for intracellular expression of IFN-γ, IL-4, and IL-17A. A profile representative of 4 mice per group is shown (**P < 0.01; mean ± SEM). (B) OT-II (WT or Camk4–/–) cells were transfected with either empty vector or pCMV-CaMK4. 4 hours after transfection cells were stimulated under Th17 conditions. After 48 hours, IL-17–producing TCRβ+CD4+ T cells were measured by intracellular cytokine staining. A profile representative of 4 mice per group is shown (*P < 0.05, **P < 0.01; mean ± SEM). (C) Naive T cells differentiated for 72 hours in Th1, Th2, or Th17 conditions in the presence of different concentrations of KN-93 from spleens of MRL/lpr mice (16 weeks old) were gated on TCRβ+CD4+ and stained for intracellular expression of IFN-γ, IL-4, and IL-17A. A profile representative of 3 independent experiments with 3 to 5 mice per group is shown (*P < 0.05, **P < 0.01; mean ± SEM). (D) ELISA of IFN-γ, IL-4, and IL-17 in supernatants of naive T cells from MRL/lpr mice differentiated for 72 hours in Th1, Th2, or Th17 conditions in the presence of different concentrations of KN-93 (μM). (*P < 0.05; mean ± SEM; n = 3–5). Data are representative of 3 independent experiments with 3 to 5 mice.