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TLR Agonists Promote Marginal Zone B Cell Activation and Facilitate T-Dependent IgM Responses¹

Anatoly V. Rubtsov^*, Cristina L. Swanson^*, Scott Troy, Pamela Strauch^*, Roberta Pelanda^* and Raul M. Torres^2,*

^* Integrated Department of Immunology, University of Colorado Denver and National Jewish Medical and Research Center, Denver, CO 80206; and West High School, Denver, CO 80204

Although IgM serves as a first barrier to Ag spreading, the cellular and molecular mechanisms following B lymphocyte activation that lead to IgM secretion are not fully understood. By virtue of their anatomical location, marginal zone (MZ) B cells rapidly generate Ag-specific IgM in response to blood-borne pathogens and play an important role in the protection against these potentially harmful Ags. In this study, we have explored the contribution of TLR agonists to MZ B cell activation and mobilization as well as their ability to promote primary IgM responses in a mouse model. We demonstrate that diverse TLR agonists stimulate MZ B cells to become activated and leave the MZ through pathways that are differentially dependent on MyD88 and IFN-β receptor signaling. Furthermore, in vivo stimulation of MZ B cells with TLR agonists led to a reduction in the expression of the sphingosine-1-phosphate (S1P) receptors expressed by MZ B cells and/or increased CD69 cell surface levels. Importantly, as adjuvants for a T cell-dependent protein Ag, TLR agonists were found to accelerate the kinetics but not magnitude of the Ag-specific IgM response. Together, these data demonstrate that in vivo TLR agonist treatment enhances the early production of Ag-specific IgM and activates MZ B cells to promote their relocation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI052310 (to R.P.) and AI052157 (to R.T.) and an American Association of Immunologists John H. Wallace Summer Fellowship (to S.T.).

² Address correspondence and reprint requests to Dr. Raul M. Torres, Integrated Department of Immunology, University of Colorado Denver and National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: torresr{at}njc.org

³ Abbreviations used in this paper: MZ, marginal zone; FO, follicular; S1P, sphingosine-1-phosphate; NP, (4-hydroxy-3-nitrophenyl)acetyl; CG, chicken -globulin; Pam₃Csk₄, N-palmitoyl(S)-[2,3-bis(palmitoyloxy)-(2, RS)-propyl]-Cys-Ser-Lys4.

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