Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses IL-2 Production and Regulatory T Cell Activity in Systemic Lupus Erythematosus

Tomohiro Koga¹, Kunihiro Ichinose², Masayuki Mizui³, José C. Crispín⁴ and George C. Tsokos⁴, ¹Medicine/Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, ²Department of Immunology and Rheumatology, Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, ³Division of Rheumatology, Department of Medicine,, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, ⁴Medicine/Rheumatology, BIDMC, Harvard Medical School, Boston, MA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Animal models, autoimmune diseases, regulatory cells and systemic lupus erythematosus (SLE), T cells

Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: T cells from patients with SLE exhibit abnormal signaling upon TCR engagement and have an altered gene expression profile. Accordingly, the regulation of several transcription factors is distorted in SLE T cells upon activation. The activity of calcium/calmodulin-dependent protein kinase IV (CaMK4) is increasedin T cells from patients with SLE and has been shown to reduce IL-2 production by promoting the effect of the transcriptional repressor cAMP responsive element modulator (CREM)-α on the IL2 promoter.

Methods: We crossed CaMK4 deficient (CaMK4^-/-) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined survival rate, autoantibody levels, immune cells subpopulations, IL-2 production and regulatory T cells (Treg) activity. The suppressive capacity of Camk4-deficient and -sufficient Tregs was evaluated in in vitro co-culture assays. To determine the relevance of our findings to human SLE, we analyzed the effect of CaMK4 inhibition in T cells from patients.

Results: Here we show that T cells from MRL/lpr mice display increased levels of CaMK4 in the nucleus and Camk4 deficiency reduces the mortality of MRL/lpr mice in a statistically significant manner. The survival rate of MRL/lpr.Camk4^-/- mice was 89% at 32 weeks of age compared to only 25% in the MRL/lpr group. The severity of the glomerulonephritis, as well as the levels of C3 deposits in the kidney and the extent of skin injury were notably decreased in MRL/lpr.Camk4^-/-mice. We demonstrate that that absence of CaMK4 restores IL-2 production, curbs increased T cell activation, and augments the number and activity of Treg. Treg from MRL/lpr.Camk4^-/-mice suppressed more efficiently the proliferation of CD4⁺CD25^– Camk4-sufficient T cells than Treg from wild type mice. Importantly, CaMK4 silencing in T cells from patients with SLE increases the generation of FoxP3⁺cells upon stimulation in the presence of TGF-β.

Conclusion: Our results demonstrate the importance of the serine/threonine kinase CaMK4 in the generation and function of regulatory T cells in patients with SLE and lupus-prone mice and its potential to serve as a therapeutic target.

Disclosure:

T. Koga,
None;

K. Ichinose,
None;

M. Mizui,
None;

J. C. Crispín,
None;

G. C. Tsokos,
None.

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