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Combined TLR/CD40 Stimulation Mediates Potent Cellular Immunity by Regulating Dendritic Cell Expression of CD70 In Vivo¹

Phillip J. Sanchez^*, Jennifer A. McWilliams^*, Catherine Haluszczak^*, Hideo Yagita and Ross M. Kedl^2,*

^* Integrated Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80206; and Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

We previously showed that immunization with a combination of TLR and CD40 agonists (combined TLR/CD40 agonist immunization) resulted in an expansion of Ag-specific CD8 T cells exponentially greater than the expansion observed to immunization with either agonist alone. We now show that the mechanism behind this expansion of T cells is the regulated expression of CD70 on dendritic cells. In contrast to previous results in vitro, the expression of CD70 on dendritic cells in vivo requires combined TLR/CD40 stimulation and is not significantly induced by stimulation of either pathway alone. Moreover, the exponential expansion of CD8⁺ T cells following combined TLR/CD40 agonist immunization is CD70 dependent. Thus, the transition from innate stimuli (TLRs) to adaptive immunity is controlled by the regulated expression of CD70.

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 funds from the University of Colorado and National Institutes of Health Grants R21AI070038-01 and R01AI06877-01.

² Address correspondence and reprint requests to Dr. Ross M. Kedl, Integrated Department of Immunology, University of Colorado, National Jewish and Medical Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: ross.kedl{at}uchsc.edu

³ Abbreviations used in this paper: DC, dendritic cell; VVova, OVA-expressing vaccina virus; poly(I:C), polyinosinic:polycytidylic acid; TNFL, TNF ligand; WT, wild type; MFI, mean fluorescence intensity; Pam₃Cys, N-palmitoyl-S-[2,3- bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteine-(S)serine-(S)lysine 4; MPL, mono-phosphoryl lipid A.

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