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Dendritic Cell Function Can Be Modulated through Cooperative Actions of TLR Ligands and Invariant NKT Cells¹

Ian F. Hermans^2,3,*,, Jonathan D. Silk^2,*, Uzi Gileadi^2,*, S. Hajar Masri^*, Dawn Shepherd^*, Kathryn J. Farrand, Mariolina Salio^* and Vincenzo Cerundolo^4,*

^* Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; and Malaghan Institute of Medical Research, Wellington, New Zealand

The quality of signals received by dendritic cells (DC) in response to pathogens influences the nature of the adaptive response. We show that pathogen-derived signals to DC mediated via TLRs can be modulated by activated invariant NKT (iNKT) cells. DC maturation induced in vivo with any one of a variety of TLR ligands was greatly improved through simultaneous administration of the iNKT cell ligand -galactosylceramide. DC isolated from animals treated simultaneously with TLR and iNKT cell ligands were potent stimulators of naive T cells in vitro compared with DC from animals treated with the ligands individually. Injection of protein Ags with both stimuli resulted in significantly improved T cell and Ab responses to coadministered protein Ags over TLR stimulation alone. Ag-specific CD8⁺ T cell responses induced in the presence of the TLR4 ligand monophosphoryl lipid A and -galactosylceramide showed faster proliferation kinetics, and increased effector function, than those induced with either ligand alone. Human DC exposed to TLR ligands and activated iNKT cells in vitro had enhanced expression of maturation markers, suggesting that a cooperative action of TLR ligands and iNKT cells on DC function is a generalizable phenomenon across species. These studies highlight the potential for manipulating the interactions between TLR ligands and iNKT cell activation in the design of effective vaccine adjuvants.

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 funded by Cancer Research U.K. (Programme Grant C399-A2291), Harry Mahon Cancer Research Trust, Medical Research Council and FP6 project DC-VACC (LSHB-CT-2003-503037) (to V.C.), and a New Zealand Health Research Council Sir Charles Hercus Fellowship (to I.F.H.).

² I.F.H., J.D.S., and U.G. contributed equally to this work.

³ Current address: Malaghan Institute of Medical Research, P.O. Box 7060, Wellington, New Zealand.

⁴ Address correspondence and reprint requests to Dr. Vincenzo Cerundolo, Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, U.K. E-mail address: vincenzo.cerundolo{at}imm.ox.ac.uk

⁵ Abbreviations used in this paper: DC, dendritic cell; -GalCer, -galactosylceramide; CMTMR, chloromethyl-benzoyl-aminotetramethyl-rhodamine; Flu-NP, influenza nucleoprotein; iNKT, invariant NKT; MPL, monophosphoryl lipid A; poly(I:C), polyinosinic polycytidylic acid; T_CM, central memory T cell; T_E, effector T cell; tg, transgenic; vacc-OVA, recombinant vaccinia virus encoding full-length chicken OVA.

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