Requirement of 8-mercaptoguanosine as a costimulus for IL-4-dependent mu to gamma1 class switch recombination in CD38-activated B cells.
Mature B-2 cells expressing surface IgM and IgD proliferate upon stimulation by CD38, CD40 or lipopolysaccharide (LPS) and differentiate into IgG1-producing plasma cells in the presence of cytokines. The process of class switch recombination (CSR) from IgM to other isotypes is highly regulated by cytokines and activation-induced cytidine deaminase (AID). Blimp-1 and XBP-1 play an essential role in the terminal differentiation of switched B-2 cells to Ig-producing plasma cells. IL-5 induces AID and Blimp-1 expression in CD38- and CD40-activated B-2 cells, leading to mu to gamma1 CSR at DNA level and IgG1 production. IL-4, a well-known IgG1-inducing factor, does not induce mu to gamma1 CSR in CD38-activated B-2 cells or Blimp-1, while IL-4 induces mu to gamma1 CSR, XBP-1 expression, and IgG1 production expression in CD40-activated B-2 cells. Interestingly, the addition of 8-mercaptoguanosine (8-SGuo) with IL-4 to the culture of CD38-activated B cells can induce mu to gamma1 CSR, Blimp-1 expression, and IgG1 production. Intriguingly, 8-SGuo by itself induces AID expression in CD38-activated B cells. However, it does not induce mu to gamma1 CSR. These results imply that the mode of B-cell activation for extracellular stimulation affects the outcome of cytokine stimulation with respect to the efficiency and direction of CSR, and the requirements of the transcriptional regulator and the generation of antibody-secreting cells. Furthermore, our data suggest the requirement of additional molecules in addition to AID for CSR.
Tsukamoto
Yumiko
Y
Division of Immunology, Department of Immunology and Microbiology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan.
Uehara
Shoji
S
Mizoguchi
Chieko
C
Sato
Atsushi
A
Horikawa
Keisuke
K
Takatsu
Kiyoshi
K
D036541:ADP-ribosyl Cyclase / Q000276:immunology*; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006151:Guanosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017578:Immunoglobulin Class Switching / Q000187:drug effects* / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D015847:Interleukin-4 / Q000008:administration & dosage*; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D013872:Thionucleosides / Q000008:administration & dosage*
D015703:Antigens, CD; D004338:Drug Combinations; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D013872:Thionucleosides; D006151:Guanosine; D015847:Interleukin-4; C037031:8-thioguanosine; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1