Autoimmunity

JNK pathway-associated phosphatase (JKAP, also named DUSP22) was originally identifi ed as a JNK activator. Recently, JKAP has been shown to play a critical role in immune regulation. In T-cell receptor (TCR) signaling, JKAP directly inactivates Lck by dephosphorylating tyrosine-394 residue. JKAP-knockout T cells display enhanced cell proliferation and cytokine production. Moreover, JKAP-knockout mice display enhanced serum levels of pro-infl ammatory cytokines (TNFα, IFNγ,IL-6, IL-17A) and autoantibodies (ANA, anti-dsDNA). JKAP-knockout mice also show enhanced T-cell-mediated immune responses and are more susceptible to experimental autoimmune encephalomyelitis (EAE). Adoptive transfer experiments further show that the recipient mice with JKAP-knockout T cells display exacerbated EAE symptoms. In addition, aged JKAP knockout mice spontaneously develop systemic infl ammation and autoimmune diseases, including nephritis. Furthermore,T-cell-specifi c JKAP mutant transgenic mice show induction of autoantibodies (ANA, anti-dsDNA) and display a lupus nephritis-like phenotype. To study the clinical relevance of JKAP downregulation in T cells, peripheral blood T cells from systemic lupus erythematosus (SLE) patients were isolated and subjected to immunoblotting. Th e data showed that JKAP protein levels in the peripheral blood T cells of SLE patients were signifi cantly decreased compared to those in healthy controls. Remarkably, JKAP downregulation in SLE T cells were correlated with proteinuria and poor renal outcome. In summary, JKAP is an important phosphatase that inactivates Lck in the turn-off stage of TCR signaling, leading to suppression of T-cellmediated autoimmunity. Furthermore, JKAP downregulation in T cells is a diagnostic and prognostic biomarker for SLE nephritis.