Human activation-induced cytidine deaminase is induced by IL-4 and negatively regulated by CD45: implication of CD45 as a Janus kinase phosphatase in antibody diversification.
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.
Zhou
Cheng
C
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.
Saxon
Andrew
A
Zhang
Ke
K
D000276:Adjuvants, Immunologic / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004794:Enzyme Repression / Q000235:genetics / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases; D003564:Cytidine Deaminase