CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells through its function as a Janus kinase phosphatase.
CD45 plays a critical regulatory role in receptor signaling through its protein tyrosine phosphatase and Janus kinase (JAK) phosphatase activities. To investigate whether CD45 also plays a regulatory role in Ig class switching in human B cells, we examined the effects of CD45 triggering on Ig class switching to IgE and its relationship with CD45 JAK phosphatase activity. Anti-CD45 triggering of CD45 significantly inhibited interleukin-4 + anti-CD40-induced switch recombination in a switch recombination vector assay in stably transfected Ramos 2G6 human B cells, as well as Ig epsilon germ-line transcription and Smu-Sepsilon switch recombination in primary human B cells. These negative regulatory effects on Ig class switching were concomitant with the ability of CD45 to dephosphorylate the induced phosphorylation of JAK1, JAK3, and signal transducer and activator of transcription 6, but not on stress-activated/mitogen-activated protein kinases. We also showed that phosphorylated JAK1 and JAK3 were directly dephosphorylated by recombinant CD45 in vitro. These results indicate that CD45 is able to function as JAK phosphatase in human B cells and that this activity is directly associated with the negative regulation of the class switch recombination to IgE. CD45 may be an appropriate target drug for modulating IgE in allergic diseases.
Yamada
Takechiyo
T
Hart and Louis Laboratory, Division of Clinical Immunology, Department of Medicine, UCLA School of Medicine, Los Angeles, California 90095-1680, USA.
Zhu
Daocheng
D
Saxon
Andrew
A
Zhang
Ke
K
D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D017493:Leukocyte Common Antigens / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008957:Models, Genetic; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens