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Published online before print July 20, 2005

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(Journal of Leukocyte Biology. 2005;78:888-897.)
© 2005 by Society for Leukocyte Biology

Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions

Hironori Tsujimoto^*,,1, Takefumi Uchida^*,, Philip A. Efron^*, Philip O. Scumpia^*, Amrisha Verma^,¶, Tadashi Matsumoto^*, Sven K. Tschoeke^*, Ricardo F. Ungaro^*, Satoshi Ono^,, Shuhji Seki^,, Michael J. Clare-Salzler, Henry V. Baker^¶, Hidetaka Mochizuki, Reuben Ramphal^,¶ and Lyle L. Moldawer^*,2

^* Departments of Surgery,
Medicine, and
^¶ Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville; and Departments of
Surgery I and
Microbiology, National Defense Medical College, Tokorozawa, Japan

²Correspondence: Department of Surgery, University of Florida College of Medicine, Room 6116, Shands Hospital, 1600 SW Archer Road, Gainesville, FL 32610-0286. E-mail: moldawer{at}surgery.ufl.edu

Flagellin, the principal component of bacterial flagella, is a ligand for Toll-like receptor 5 (TLR5) or TLR11 and contributes to systemic inflammation during sepsis through activation of dendritic cells (DCs) and other cells of the innate immune system. Here, we report that flagellin and the TLR4 ligand, lipopolysaccharide (LPS), induced phenotypic and functional maturation of murine bone marrow-derived DCs and enhanced DC accumulation in the draining popliteal lymph node following their footpad injection. It is interesting that flagellin injection enhanced myeloid (CD8^–1) and plasmacytoid (plasmacytoid DC antigen⁺ B220⁺) DC subsets, whereas LPS only increased myeloid DCs in the draining lymph node. In addition, the footpad injection of flagellin or LPS induced significant CD4⁺ T cell activation in the draining popliteal lymph node, as judged by increased CD69 or CD25 expression. We illustrate, for the first time, that flagellin also increases natural killer (NK) cell number and activation status in the draining lymph node after footpad injection. Using coculture with enriched carboxy-fluorescein diacetate succinimidyl ester-labeled NK cells, flagellin-treated DCs induce significant NK cell proliferation and activation. In fact, direct treatment of NK cells with flagellin induces a greater increase in cell proliferation than treatment with LPS. In contrast, flagellin treatment of NK cells was not a strong inducer of interferon- (IFN-) production, indicating that NK cell proliferation and IFN- production may be regulated differentially. These data suggest that flagellin is a capable maturation agent for murine myeloid-derived DCs, and flagellin-activated DCs and flagellin itself are potent inducers of NK cell proliferation.

Key Words: Toll-like receptor • migration • chemokine • chemokine receptor

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