Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN.
Detailed information of human B cell activation via TLR may lead to a better understanding of B cell involvement in autoimmunity and malignancy. In this study we identified a fundamental difference in the regulation of TLR7- and TLR9-mediated B cell stimulation: whereas the induction of polyclonal naive B cell proliferation by the TLR7 ligands resiquimod (R848) and loxoribine required the presence of plasmacytoid dendritic cells (PDCs), activation via the TLR9 ligand CpG was independent of PDCs. We found that PDC-derived type I IFN enhanced TLR7 sensitivity of B cells by selectively up-regulating TLR7 expression. In contrast the expression levels of TLR9 and of other TLRs studied remained unchanged. In the presence of type I IFN, TLR7 ligation triggered polyclonal B cell expansion and B cell differentiation toward Ig-producing plasma cells; notably, this occurred independently of T cell help and B cell Ag. Human B cells did not respond to ligands of other TLRs including TLR2, TLR4 and TLR6 with and without type I IFN. In conclusion, our results reveal a distinct regulation of TLR7 and TLR9 function in human B cells and highlight TLR7 and TLR9 as unique targets for therapeutic intervention in B cell-mediated immunity and disease.
Bekeredjian-Ding
Isabelle Béatrice
IB
Department of Internal Medicine, Division of Clinical Pharmacology, University of Munich, Munich, Germany.
Berkeredjian-Ding
Isabelle Béatrice
IB
Wagner
Moritz
M
Hornung
Veit
V
Giese
Thomas
T
Schnurr
Max
M
Endres
Stefan
S
Hartmann
Gunther
G
D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D001773:Blood Cells; D002454:Cell Differentiation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000235:genetics
D007370:Interferon Type I; D008024:Ligands; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors