Differential cytokine production and bystander activation of autoreactive B cells in response to CpG-A and CpG-B oligonucleotides.
Synthetic oligonucleotides containing CpG motifs have been shown to induce proliferation, differentiation, and cytokine production in B cells, macrophages, and dendritic cells through a TLR9-dependent mechanism. A class (CpG-A) and B class (CpG-B) oligonucleotides display distinct physical properties. CpG-A, but not CpG-B, can multimerize to form exceedingly large lattices. CpG-A cannot effectively activate B cells but does induce plasmacytoid dendritic cells to produce high levels of IFNalpha, while CpG-B is a potent B cell mitogen. In this study, we report that CpG-A is internalized by B cells, and CpG-A and CpG-B accumulate in distinct intracellular compartments. When present in the form of an immune complex (CpG-A IC), CpG-A is taken up more efficiently by AM14 IgG2a-specific B cells, and elicits a robust TLR9-dependent B cell proliferative response. B cells proliferating comparably and in a TLR9-dependent fashion in response to CpG-A IC and CpG-B exhibited distinct cytokine profiles. CpG-A IC induced enhanced production of RANTES and markedly reduced levels of IL-6 when compared with CpG-B. We also found that engagement of the AM14 BCR by a protein IC, which cannot by itself induce proliferation, promoted TLR9-dependent but BCR-independent proliferation by bystander CpG-A or fragments of mammalian dsDNA. These data identify direct and indirect mechanisms by which BCR engagement facilitates access of exogenous ligands to TLR9-associated compartments and subsequent B cell activation.
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
Ana M
AM
Avalos
Eicke
E
Latz
Betty
B
Mousseau
Sean R
SR
Christensen
Mark J
MJ
Shlomchik
Frances
F
Lund
Ann
A
Marshak-Rothstein
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000936:Antigen-Antibody Complex; C408982:CPG-oligonucleotide; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D011947:Receptors, Antigen, B-Cell; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9