HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900974v1 183/6/3634    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Pulko, V. Articles by Dong, H. PubMed PubMed Citation Articles by Pulko, V. Articles by Dong, H.

TLR3-Stimulated Dendritic Cells Up-regulate B7-H1 Expression and Influence the Magnitude of CD8 T Cell Responses to Tumor Vaccination¹

Vesna Pulko, Xin Liu^*, Christopher J. Krco^*, Kimberley J. Harris^*, Xavier Frigola^*, Eugene D. Kwon^* and Haidong Dong^2,*,

Departments of ^* Urology and Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905

Agonists of TLR have been explored as vaccine adjuvants for tumor immunotherapy. However, their immunological consequences are not fully understood. Although TLR signaling increases the functional potential of dendritic cells (DCs) for priming T cells, coinduction of potentially negative immunoregulatory capacities may impair effector T cell generation. We examined the expression and function of B7 family costimulatory molecules on DCs after activation with the TLR3 agonist, polyinosinic:polycytidylic acid. We demonstrated that polyinosinic:polycytidylic acid consistently up-regulated both B7-2 and B7-H1 molecules on resident, migratory DCs from spleen and lymph nodes. Depletion or blockade of B7-H1 on activated DCs increased the magnitude of effector CD8 T cell expansion. DC-based or protein-based tumor vaccines, in combination with B7-H1 blockade, induced strong effector CD8 T cell responses, resulting in protective immunity against newly established tumors. Our studies suggest that TLR3 signaling has the potential to up-regulate both positive and negative coregulatory molecules on APCs. Selective blockade of negative regulatory molecules in combination with TLR3 agonist may be an effective strategy for increasing the efficacy of tumor vaccines.

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 Mayo Foundation Career Development Award (to H.D.) and in part by a generous donation from the Richard M. Schulze Family Foundation (to E.D.K.), as well as by National Institutes of Health/National Cancer Institute Grant R01 CA134345.

² Address correspondence and reprint requests to Dr. Haidong Dong, Departments of Urology and Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905. E-mail address: dong.haidong{at}mayo.edu

³ Abbreviations used in this paper: DC, dendritic cell; Act-mOVA, actin promotor-driven membrane-bound chicken ovalbumin; KO, knockout; poly(I:C), polyinosinic:polycytidylic acid; WT, wild type; CFDA-SE, carboxyfluorescein diacetate succinimidyl ester; TRP2, tyrosinase-related protein 2.