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T cells from patients with systemic lupus erythematosus exhibit a notable array of defects that probably contribute to the origin and development of the disease. Such abnormalities include an abnormal response to stimulation, aberrant expression of molecules that play key roles in intracellular signalling pathways, altered transcription factor activation and binding, and skewed gene expression. The combination of these alterations leads the cell to the expression of a particular phenotype that intense research has gradually uncovered over the last years. The aim of this article is to review the findings that have allowed us to better understand the behaviour of the lupus T cell and highlight the molecules that represent potential therapeutic targets.

Background IL-17 producing T helper (Th17) cells have been closely associated with the development of organ damage in inflammatory and autoimmune diseases. We have previously reported that Calcium/calmodulin-dependent protein kinase IV (CaMK4) plays a crucial role in Th17 cell differentiation invitro and invivo and suggested that CaMK4 inhibition ameliorates clinical and pathological findings in experimental autoimmune encephalomyelitis (EAE) and MRL/lpr mice (1). We have also shown that Il-17 is important in the expression of anti-glomerular basement membrane Ab-induced glomerulonephritis (AIGN) (2). However, the effect of CaMK4 on recruitment of pathogenic T cells to target tissues in inflammatory settings has not been studied. Objectives The aim of this study is to determine the role of CaMK4 in the infiltration of inflammatory cells to target tissues and to explore its mechanism. Methods We induced experimental AIGN in Camk4 sufficient or deficient mice and compared the kidney injury including the number of IL-17 producing cells and the expression of CCR6 and CCL20 in both groups. We also evaluated the effect of KN-93, a compound of CaMK4 antagonist in this AIGN model. Results Camk4 deficient mice displayed less glomerular injury and less proteinuria at day 14 and at day 21 after induction of AIGN. The expression of CCR6 and CCL20 in inflamed kidney is lower in Camk4 deficient mice. Kidney infiltration by Th17 producing CD4+ T cells was decreased significantly in Camk4 deficient mice, suggesting that CaMK4 facilitated AIGN damage by promoting local inflammatory cells accumulation. In line with these observations, KN-93 treatment improved clinical and pathological finings in mice induced AIGN at dose dependent manner. Conclusions Collectively, our results indicate that CaMK4 inhibition might be a novel therapeutic strategy of Th17 cells-mediated inflammatory diseases. References CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. Koga T, Hedrich CM, Mizui M, Yoshida N, Otomo K, Lieberman LA, Rauen T, Crispin JC, Tsokos GC. J Clin Invest. 2014 May 1;124(5):2234-45. Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism.Crispin JC, Apostolidis SA, Rosetti F, Keszei M, Wang N, Terhorst C, Mayadas TN, Tsokos GC.J Immunol. 2012 Apr 15;188(8):3567-71. Disclosure of Interest None declared

Background Autoimmune diseases such as systemic lupus erythematosus (SLE) display quantitative (1) and/or qualitative (2) deficiencies of Foxp3+ regulatory T (Treg) cells and this is considered to contribute to immune dysregulation and organ damage (3). Calcium/calmodulin-dependent protein kinase IV (CaMK4) is expressed at increased levels in T cells from SLE patients (4) and lupus-prone mice (5). Objectives Treg are pivotal for the maintenance of peripheral tolerance and prevent development of autoimmune diseases. We have reported that CaMK4 deficient MRL/ lpr mice display less disease activity by promoting IL-2 production and increasing the activity of Treg cells. To further define the mechanism of CaMK4 on Treg cells in SLE, we used the Foxp3 -GFP reporter mice and treated them with KN-93, an inhibitor of CaMK4. Methods We generated MRL/ lpr Foxp3- GFP mice to record Treg cells; stimulated naive CD4+ T cells from MRL/ lpr Foxp3- GFP mice under Treg polarizing conditions in the absence or presence of KN-93; evaluated the number of GFP` positive cells in lymphoid organs and examined skin and kidney pathology at 16 week of age. We also examined the infiltration of cells and recruitment of Treg cells in the kidney. Results We show that culture of MRL/ lpr Foxp3- GFP T cells in the presence of KN-93 promotes Treg differentiation in a dose dependent manner (Fig. F). Treatment of MRL/ lpr Foxp3- GFP mice with KN-93 results in significant induction of Treg cells in the spleen, peripheral lymph nodes (Fig. B-E) and peripheral blood (Fig. A and B) and this is accompanied by decreased skin and kidney damage. Notably, KN-93 clearly diminishes the accumulation of inflammatory cells along with reciprocally increased Treg cells in target organ. ![Figure 1][1] Figure 1 Conclusions Our results indicate that KN-93 treatment enhances the generation of Treg cells in vitro and in vivo highlighting its potential therapeutic use for the treatment of human autoimmune diseases. References 1. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579-88. 2. Yan B, Ye S, Chen G, Kuang M, Shen N, Chen S. Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum. 2008;58(3):801-12. 3. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636-45. 4. Juang YT, Wang Y, Solomou EE, Li Y, Mawrin C, Tenbrock K, et al. Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J Clin Invest. 2005;115(4):996-1005. 5. Koga T, Ichinose K, Mizui M, Crispin JC, Tsokos GC. Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses IL-2 Production and Regulatory T Cell Activity in Lupus. J Immunol. 2012;189(7):3490-6. Acknowledgements This work was supported by NIH grants RO1 AI R01AI085567 and AR064350. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2491 [1]: pending:yes