OP0193 CAMP RESPONSE ELEMENT MODULATOR (CREM)A INDUCES DUAL SPECIFICITY PROTEIN PHOSPHATASE (DUSP)4 THROUGH EPIGENETIC REMODELING, PROMOTING IL-17A AND REDUCING IL-2 EXPRESSION IN T CELLS
Authors: Sigrun Hofmann, Katrin Maebert, Franz Kapplusch, Susanne Russ, Christian Hedrich
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Tissue inflammation and organ damage in systemic lupus erythematosus (SLE) have been linked to effector T cells that are characterized by increased IL-17A and reduced IL-2 production(1). T cells from patients with SLE express increased levels of the transcription factor cAMP response element modulator (CREM)α that contributes to altered cytokine expression(1-3). However, the exact molecular events contributing to dysregulated IL-17A and IL-2 expression are incompletely understood. <h3>Objectives</h3> To investigate molecular events that promote effector T cells in health and disease. The definition of molecular regulators of effector T cell generation and activity may deliver new biomarkers and potential therapeutic targets in disorders characterized by altered effector T cell function, including (but not limited to) SLE. <h3>Methods</h3> Using CRISPR/Cas9 genome editing and lentiviral transduction, we generated CREMα deficient or overexpressing Jurkat T cells. Gene expression profiles in Jurkat and primary human CD4+ T cells were assessed by qRT-PCR and mRNA probe-based hybridization techniques. Gene regulation events were investigated using luciferase reporter assays (<i>trans</i>-activation) and ChIP. Interactions between CREMα and the transcriptional co-activator p300 were assessed using proximity ligation assays and p300 knock-down with siRNAs. <h3>Results</h3> We link CREMα production in effector CD4<sup>+</sup> T cells with increased expression of dual specificity protein phosphatase (DUSP)4. Using genetically modified Jurkat T cells, we demonstrate that CREMα induces DUSP4 through recruitment of the transcriptional co-activator p300 and histone H3K18 acetylation. Using DUSP4 transfection models and genetically modified Jurkat T cells, we support previous reports suggesting that DUSP4 induces IL-17A while limiting IL-2 expression. Furthermore, we demonstrate that CD4<sup>+</sup> T cells from patients with juvenile-onset SLE share the phenotype with CREMα over-expressing CD4<sup>+</sup> T cells with increased DUSP4 expression that contributes to imbalanced IL-17A and IL-2 production. <h3>Conclusion</h3> Collectively, our results deliver previously unknown CREMα-mediated molecular mechanisms promoting effector T cells and support the central involvement of CREMα in the pathophysiology of SLE. CREMα and DUSP4 may prove valuable as disease biomarkers and/or targets in the search for individualized and target-directed treatments. <h3>References</h3> [1] SLE-Associated Defects Promote Altered T Cell Function. Crispin JC, Hedrich CM, et al. Crit Rev Immunol. 2017;37(1):39-58. [2] cAMP responsive element modulator: a critical regulator of cytokine production. Rauen T, Hedrich CM, et al. Trends Mol Med. 2013 Apr;19(4):262-9. [3] cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus. Hedrich CM, Crispin JC, et al. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16606-11. <h3>Acknowledgement</h3> This is a summary of independent research funded by the Fritz-Thyssen-Foundation and carried out at the National Institute of Health Research (NIHR) Alder Hey Clinical Research Facility. The views expressed are those of the authors. <h3>Disclosure of Interests</h3> Sigrun Hofmann: None declared, Katrin Maebert: None declared, Franz Kapplusch: None declared, Susanne Russ: None declared, Christian Hedrich Grant/research support from: Novartis Pharmaceuticas for Research study on effector T cells in psoriasis, Speakers bureau: In 2016: Roche Pharmaceuticals, RheumatoLogisch, Dresden, Germany; Novartis, Advisory board &gt; Travel costs.