Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion.
Activation-induced deaminase (AID) is expressed in activated B lymphocytes and initiates somatic hypermutation and class switch recombination. To determine if different stimuli affect the expression and function of AID, we monitored AID activity in murine B cells stimulated ex vivo with various ligands. AID was rapidly expressed at both the RNA and protein levels following stimulation with LPS, LPS plus IL-4, and anti-CD40 plus IL-4, but was delayed after stimulation with anti-IgM plus IL-4. By day 4, AID was expressed in all groups; however, cells stimulated with anti-IgM plus IL-4 did not undergo switch recombination. These cells expressed normal levels of gamma 1 germline transcripts, implying that the gamma 1 switch region was accessible. Furthermore, switching was suppressed by the addition of anti-IgM to cells stimulated with LPS plus IL-4 or anti-CD40 plus IL-4, even though AID was expressed. The lack of class switch recombination could be reversed by inhibition of phosphatidylinositol 3-kinase (PI3K). This suggests that activation through the B cell receptor induces PI3K, which interferes with the function of AID.
Heltemes-Harris
Lynn M
LM
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Gearhart
Patricia J
PJ
Ghosh
Paritosh
P
Longo
Dan L
DL
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019013:CD40 Antigens / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D003564:Cytidine Deaminase / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007075:Immunoglobulin M / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019013:CD40 Antigens; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors; D019869:Phosphatidylinositol 3-Kinases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase