Control of IL-2/ regulatory T cell axis by Calcium/calmodulin-dependent protein kinase type IV plays a key role in lupus-prone mice (72.4)

Abstract

Abstract Objective. Dysfunction of regulatory CD4+CD25+FoxP3+ T (Treg) cells has been detected in autoimmune diseases. IL-2 is critical for the development, survival, and function of Treg cells. Increased levels of Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) cause defective IL-2 production in T cells from patients with SLE. Methods. We crossed CaMKIV deficient (CaMK4-/-) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined survival rate, autoantibody levels, immune cells subpopulations, pro-inflammatory cytokine production and T cell function. Results. The survival rate was significantly higher in MRL/lpr.CaMK4-/- mice than in wild type MRL/lpr mice at 32 weeks (89% versus 25%, p<0.05). MRL/lpr.CaMK4-/- mice displayed decreased titers of anti-DNA antibodies, reduced numbers of double negative T cell, CD4+ activated/memory cells in the spleen. The production of IL-2 in response to anti-CD3/28 antibody by CD4+ T cells was restored in MRL/lpr.CaMK4-/- mice, and this was associated with decreased levels of phosphorylated cAMP response element modulator (CREM) in the nucleus. Notably, the number of Treg cells was increased in MRL/lpr.CaMKiv-/- mice. We further confirmed silencing of CaMKIV resulted in overexpression of FoxP3 gene in human SLE T cells. Conclusion. Our results suggest that CaMKIV is important in the expression of the disease in lupus-prone mice, and we propose that CaMKIV represents a valuable target for treatment in autoimmune diseases.