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Mucosally Delivered Dendritic Cells Activate T Cells Independently of IL-12 and Endogenous APCs¹

Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, and M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada

In vitro manipulated dendritic cells (DC) have increasingly been used as a promising vaccine formulation against cancer and infectious disease. However, improved understanding of the immune mechanisms is needed for the development of safe and efficacious mucosal DC immunization. We have developed a murine model of respiratory mucosal immunization by using a genetically manipulated DC vaccine. Within 24 h of intranasal delivery, the majority of vaccine DCs migrated to the lung mucosa and draining lymph nodes and elicited a significant level of T cells capable of IFN- secretion and CTL in the airway lumen as well as substantial T cell responses in the spleen. And such T cell responses were associated with enhanced protection against respiratory mucosal intracellular bacterial challenge. In comparison, parenteral i.m. DC immunization did not elicit marked airway luminal T cell responses and immune protection regardless of strong systemic T cell activation. Although repeated mucosal DC delivery boosted Ag-specific T cells in the airway lumen, added benefits to CD8 T cell activation and immune protection were not observed. By using MHC-deficient vaccine DCs, we further demonstrated that mucosal DC immunization-mediated CD8 and CD4 T cell activation does not require endogenous DCs. By using IL-12-deficient vaccine DCs, we also observed that IL-12^–/– DCs failed to migrate to the lymph nodes but remained capable of T cell activation. Our observations indicate that mucosal delivery of vaccine DCs represents an effective approach to enhance mucosal T cell immunity, which may operate independent of vaccine IL-12 and endogenous DCs.

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 study is supported by funds from the Canadian Institutes for Health Research.

² Address correspondence and reprint requests to Dr. Zhou Xing, Room 4012-MDCL, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. E-mail address: xingz{at}mcmaster.ca

³ Abbreviations used in this paper: DC, dendritic cell; BCG, Bacillus Calmette-Guérin; i.n., intranasal; MHCII, MHC class II; MHCI, MHC class I; BAL, bronchoalveolar lavage; LN, lymph node; cLN, cervical LN; mLN, mediastinal LN; pLN, popliteal LN; i.t., intratracheal; ICCS, intracellular cytokine staining; wt, wild type.