Session 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.
J. C. Crispín,
G. C. Tsokos,
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/calciumcalmodulin-dependent-protein-kinase-iv-suppresses-il-2-production-and-regulatory-t-cell-activity-in-systemic-lupus-erythematosus/