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Cutting Edge: TLR Ligands Increase TCR Triggering by Slowing Peptide-MHC Class I Decay Rates¹

Brian D. Rudd^*, James D. Brien, Miles P. Davenport and Janko Nikolich-ugich^2,*,

^* Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85718; Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006; and Department of Haematology, Prince of Wales Hospital and Centre for Vascular Research, University of New South Wales, Kensington, New South Wales, Australia

TLR ligands are among the key stimuli driving the optimal dendritic cell (DC) maturation critical for strong and efficacious T cell priming. In this study, we show that part of this effect occurs via increased TCR triggering. Pretreatment of DCs with TLR ligands resulted in the triggering of many more TCRs in responding CD8⁺ T cells. Importantly, even when DCs expressed the same amount of cognate peptide-MHC (pMHC) molecules, TLR ligand treatment resulted in down-regulation of larger numbers of TCR molecules. This was independent of the up-regulation of costimulatory, adhesion or cytokine molecules or the amount of noncognate pMHCs. Rather, DCs pretreated with TLR ligands exhibited increased stability of cognate pMHCs, enabling extended TCR triggering. These findings are of potential importance to T cell vaccination.

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 U.S. Public Health Service Grants AI-066096 (to J.N.-.) and RR-0163 (to the Oregon National Primate Research Center) from the National Institute of Allergy and Infectious Diseases and National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Janko Nikolich-ugich, Department of Immunobiology, University of Arizona College of Medicine, P.O. Box 249221, 1501 North Campbell Avenue, Tucson, AZ, 85724. E-mail address: nikolich{at}email.arizona.edu

³ Abbreviations used in this paper: pMHC, peptide-MHC complex; BM-DC, bone marrow-derived DC; DC, dendritic cell; FCM, flow cytofluorometric analysis; gB-8p, gB peptide; MFI, mean fluorescence intensity.