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Differential Cytokine Production and Bystander Activation of Autoreactive B Cells in Response to CpG-A and CpG-B Oligonucleotides¹

Ana M. Avalos,^* Eicke Latz, Betty Mousseau, Sean R. Christensen, Mark J. Shlomchik, Frances Lund, and Ann Marshak-Rothstein^2*

*Department of Microbiology, Boston University School of Medicine, Boston, MA 02118; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY 14620; and Section of Immunology, Yale University School of Medicine, New Haven, CT 06520

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 IFN, 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.

² Address correspondence and reprint requests to Dr. Ann Marshak-Rothstein, Department of Microbiology, Boston University School of Medicine, Boston, MA 02118. E-mail address: amrothst{at}bu.edu

¹ This work was supported by National Institutes of Health Grants AR050256 and AR35230 (to A.M.R.) and RO1 AI068056 (to F.L.).