Zhou Cheng, Saxon Andrew, Zhang Ke
Hart and Louis Laboratory, Division of Clinical Immunology/Allergy, Department of Medicine, University of California-Los Angeles School of Medicine, 52-175 Center for Health Science, 10833 Le Conte Avenue, Los Angeles, CA 90095-1680, USA.
J Immunol. 2003 Feb 15;170(4):1887-93. doi: 10.4049/jimmunol.170.4.1887.
Activation-induced cytidine deaminase (AID) plays critical roles in Ig class switch recombination and V(H) gene somatic hypermutation. We investigated the role of IL-4 in AID mRNA induction, the signaling transduction involved in IL-4-mediated AID induction, and the effect of CD45 on IL-4-dependent AID expression in human B cells. IL-4 was able to induce AID expression in human primary B cells and B cell lines, and IL-4-induced AID expression was further enhanced by CD40 signaling. IL-4-dependent AID induction was inhibited by a dominant-negative STAT6, indicating that IL-4 induced AID expression via the Janus kinase (JAK)/STAT6 signaling pathway. Moreover, triggering of CD45 with anti-CD45 Abs can inhibit IL-4-induced AID expression, and this CD45-mediated AID inhibition correlated with the ability of anti-CD45 to suppress IL-4-activated JAK1, JAK3, and STAT6 phosphorylations. Thus, in humans, IL-4 alone is sufficient to drive AID expression, and CD40 signaling is required for optimal AID production; IL-4-induced AID expression is mediated via the JAK/STAT signaling pathway, and can be negatively regulated by the JAK phosphatase activity of CD45. This study indicates that the JAK phosphatase activity of CD45 can be induced by anti-CD45 Ab treatment, and this principle may find clinical application in modulation of JAK activation in immune-mediated diseases.
活化诱导的胞苷脱氨酶（AID）在Ig类别转换重组和V(H)基因体细胞高频突变中发挥关键作用。我们研究了白细胞介素-4（IL-4）在AID mRNA诱导中的作用、IL-4介导的AID诱导所涉及的信号转导，以及CD45对人B细胞中IL-4依赖性AID表达的影响。IL-4能够在人原代B细胞和B细胞系中诱导AID表达，并且CD40信号进一步增强了IL-4诱导的AID表达。显性负性STAT6抑制了IL-4依赖性AID诱导，表明IL-4通过Janus激酶（JAK）/STAT6信号通路诱导AID表达。此外，用抗CD45抗体触发CD45可抑制IL-4诱导的AID表达，并且这种CD45介导的AID抑制与抗CD45抑制IL-4激活的JAK1、JAK3和STAT6磷酸化的能力相关。因此，在人类中，单独的IL-4足以驱动AID表达，并且最佳的AID产生需要CD40信号；IL-4诱导的AID表达通过JAK/STAT信号通路介导，并且可被CD45的JAK磷酸酶活性负调控。本研究表明，抗CD45抗体处理可诱导CD45的JAK磷酸酶活性，并且这一原理可能在免疫介导疾病中JAK激活的调节方面具有临床应用价值。
