Toll-like receptor 7 cooperates with IL-4 in activated B cells through antigen receptor or CD38 and induces class switch recombination and IgG1 production

作者：Tsukamoto Yumiko; Nagai Yoshinori; Kariyone Ai; Shibata Takuma; Kaisho Tsuneyasu; Akira Shizuo; Miyake Kensuke; Takatsua Kiyoshi^*

来源：Molecular Immunology, 2009, 46(7): 1278-1288.

DOI：10.1016/j.molimm.2008.11.022

• Class switch recombination (CSR)
• Toll-like receptor 7 (TLR7)
• 8-Mercaptoguanosine (8-SGuo)
• Interleukin-4 (IL-4)
• CD38
• AID
• Blimp-1

IL-4 and 8-mercaptoguanosine (8-SGuo) stimulation of CD38-activated B cells induces mu to gamma 1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Although some of signaling events initiated by IL-4 in activated B cells have been characterized, the involvement of TLR/MyD88 and Btk pathway in IL-4-dependent mu to gamma 1 CSR has not been thoroughly evaluated. In this study, we characterized receptors for 8-SGuo and differential roles of 8-SGuo and IL-4 in the induction and mu to gamma 1 CSR and IgG1 production. The role of TLR7 and MyD88 in 8-SCuo-induced AID expression and mu to gamma 1 CSR was documented, as 8-SGuo did not act on CD38-stimulated splenic B cells from Tlr7(-/-) and Myd88(-/-) mice. CD38-activated B cells from Btk-deficient mice failed to respond to TLR7 ligands for the AID expression and CSR, indicating that Btk is also indispensable for the system. Stimulation of CD38-activated B cells with 8-SGuo induced significant AID expression and DNA double strand breaks, but IL-4 stimulation by itself did not trigger mu to gamma 1 CSR. Intriguingly, the mu to gamma 1 CSR in the B cells stimulated with CD38 and 8-SGuo totally depends on IL-4 stimulation. Similar results were obtained in the activated B cells through BCR and loxoribine, a well-known TLR7 ligand, in place of 8-SCuo. In vivo administration of TLR7 ligand and anti-CD38 antibody induced the generation of CD138( ) IgG1( ) cells. These results indicate that TLR7 is a receptor for 8-SGuo and plays an essential role in the AID and Blimp-1 expression; however it is not enough to complete mu to gamma 1 CSR in CD38-activated B cells. IL-4 may be required for the induction of DNA repair system together with AID for the completion of CSR.

• 出版日期2009-4
• 单位河北医科大学