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Direct Stimulation of tlr5^+/+ CD11c⁺ Cells Is Necessary for the Adjuvant Activity of Flagellin¹

John T. Bates^*, Satoshi Uematsu, Shizuo Akira and Steven B. Mizel^2,*

^* Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

Flagellin is a highly effective adjuvant, but the cellular mechanism underlying this activity remains uncertain. More specifically, no consensus exists as to whether flagellin activates dendritic cells (DC) directly or indirectly. Intramuscular immunization with flagellin-OVA fusion protein resulted in enhanced in vivo T cell clustering in draining lymph nodes and IL-2 production by OVA-specific CD4⁺ T cells. Immunization with flagellin-OVA also triggered greater levels of Ag-specific CD4⁺ T cell proliferation than immunization with flagellin and OVA as separate proteins. To determine whether flagellin, in the context of a fusion protein with OVA, was acting directly on DC, we used a combination of CD4⁺ T cell adoptive transfers and bone marrow chimera mice in which the presence or absence of potential tlr5^+/+ CD11c⁺ cells was controlled by injection of diphtheria toxin. The Ag-specific CD4⁺ T cell response in mice with CD11c⁺ cells from a tlr5^–/– background and mixed populations of all other hematopoietic cells was dramatically reduced in comparison to mice that had DC from tlr5^–/– and wild-type backgrounds. Immunization of MyD88^–/–tlr5^+/+ mice revealed that the enhanced response following immunization with flagellin-OVA is dependent on signaling via the TLR5-MyD88 pathway as well as enhanced Ag uptake and processing resulting from Ag targeting via TLR5. In summary, our data are consistent with the conclusion that direct stimulation of tlr5^+/+ CD11c⁺ cells is necessary for the adjuvant activity of a flagellin fusion protein and that this adjuvant effect requires signaling through TLR5.

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 a grant from the National Institutes of Health (P01 AI 60642; to S.B.M.).

² Address correspondence and reprint requests to Dr. Steven B. Mizel, Department of Microbiology and Immunology, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail address: smizel{at}wfubmc.edu

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived murine DC; DTR, diptheria toxin receptor.