Zhang Yongliang, Reynolds Joseph M, Chang Seon Hee, Martin-Orozco Natalia, Chung Yeonseok, Nurieva Roza I, Dong Chen
Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Biol Chem. 2009 Nov 6;284(45):30815-24. doi: 10.1074/jbc.M109.052472. Epub 2009 Sep 10.
MAPKs are evolutionarily conserved immune regulators. MAPK phosphatases (MKPs) that negatively regulate MAPK activities have recently emerged as critical players in both innate and adaptive immune responses. MKP-1, also known as DUSP1, was previously shown to negatively regulate innate immunity by inhibiting pro-inflammatory cytokine production. Here, we found that MKP-1 is necessary in T cell activation and function. MKP-1 deficiency in T cells impaired the activation, proliferation, and function of T cells in vitro, associated with enhanced activation of JNK and reduced NFATc1 translocation into the nucleus. Consistently, MKP-1(-/-) mice were defective in anti-influenza immunity in vivo and resistant to experimental autoimmune encephalomyelitis. Our results thus demonstrate that MKP-1 is a critical positive regulator of T cell activation and function and may be targeted in treatment of autoimmune diseases.
丝裂原活化蛋白激酶（MAPKs）是进化上保守的免疫调节因子。负向调节MAPK活性的MAPK磷酸酶（MKPs）最近已成为先天性和适应性免疫反应中的关键角色。MKP-1，也称为双特异性磷酸酶1（DUSP1），先前已表明其通过抑制促炎细胞因子的产生来负向调节先天性免疫。在此，我们发现MKP-1在T细胞活化和功能中是必需的。T细胞中MKP-1的缺陷损害了T细胞在体外的活化、增殖和功能，这与JNK的活化增强和NFATc1向细胞核的转位减少有关。一致地，MKP-1基因敲除（-/-）小鼠在体内抗流感免疫方面存在缺陷，并且对实验性自身免疫性脑脊髓炎具有抗性。因此，我们的结果表明MKP-1是T细胞活化和功能的关键正向调节因子，并且可能是自身免疫性疾病治疗的靶点。
