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Variable Requirement of Dendritic Cells for Recruitment of NK and T Cells to Different TLR Agonists¹

Takefumi Uchida^2,*,, Philip O. Scumpia^2,*, Donna M. Murasko, Shuhji Seki, Susan Woulfe^¶, Michael J. Clare-Salzler and Lyle L. Moldawer^3,*

^* Department of Surgery and Department of Pathology, University of Florida College of Medicine, Gainesville, FL 32610; Department of Microbiology, National Defense Medical College, Tokorozawa, Japan; Department of Microbiology, Drexel University, Philadelphia, PA 19104; and ^¶ 3M Pharmaceuticals, St. Paul, MN 55144

TLRs initiate the host immune response to microbial pathogens by activating cells of the innate immune system. Dendritic cells (DCs) can be categorized into two major groups, conventional DCs (including CD8⁺ and CD8^– DCs) and plasmacytoid DCs. In mice, these subsets of DCs express a variety of TLRs, with conventional DCs responding in vitro to predominantly TLR3, TLR4, TLR5, and TLR9 ligands, and plasmacytoid DCs responding mainly to TLR7 and TLR9 ligands. However, the in vivo requirement of DCs to initiate immune responses to specific TLR agonists is not fully known. Using mice depleted of >90% of CD11c⁺ MHC class II⁺ DCs, we demonstrate that cellular recruitment, including CD4⁺ T cell and CX5⁺DX5⁺ NK cell recruitment to draining lymph nodes following the footpad administration of TLR4 and TLR5 agonists, is dramatically decreased upon reduction of DC numbers, but type I IFN production can partially substitute for DCs in response to TLR3 and TLR7 agonists. Interestingly, TLR ligands can activate T cells and NK cells in the draining lymph nodes, even with reduced DC numbers. The findings reveal considerable plasticity in the response to TLR agonists, with TLR4 and TLR5 agonists sharing the requirement of DCs for subsequent lymph node recruitment of NK and T cells.

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 Grant R37 GM-40586 from the National Institute of General Medical Sciences, U.S. Public Health Service.

² T.U. and P.O.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Lyle L. Moldawer, Department of Surgery, University of Florida College of Medicine, 1600 Southwest Archer Road, Room 6116, Gainesville, FL 32610-0286. E-mail address: moldawer{at}surgery.ufl.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; PDCA, plasmacytoid DC Ag-1; DT, diphtheria toxin; poly(I:C), polyinosinic-polycytidylic acid.