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.
IL-4 and 8-mercaptoguanosine (8-SGuo) stimulation of CD38-activated B cells induces mu to gamma1 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 gamma1 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 gamma1 CSR and IgG1 production. The role of TLR7 and MyD88 in 8-SGuo-induced AID expression and mu to gamma1 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 gamma1 CSR. Intriguingly, the mu to gamma1 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-SGuo. 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 gamma1 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.
Tsukamoto
Yumiko
Y
Division of Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Nagai
Yoshinori
Y
Kariyone
Ai
A
Shibata
Takuma
T
Kaisho
Tsuneyasu
T
Akira
Shizuo
S
Miyake
Kensuke
K
Takatsu
Kiyoshi
K
D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004357:Drug Synergism; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D007074:Immunoglobulin G / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008562:Membrane Glycoproteins / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000906:Antibodies; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C513258:Prdm1 protein, mouse; D011947:Receptors, Antigen, B-Cell; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014157:Transcription Factors; D006151:Guanosine; D015847:Interleukin-4; C068562:loxoribine; D000074462:Positive Regulatory Domain I-Binding Factor 1; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase