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Targeting the Gut Vascular Endothelium Induces Gut Effector CD8 T Cell Responses Via Cross-Presentation by Dendritic Cells¹

Dorothee Bourges^*, Yifan Zhan^*, Jamie L. Brady^*, Hal Braley, Irina Caminschi^*, Sandro Prato^*,, José A. Villadangos^* and Andrew M. Lew^2,*

^* The Walter and Eliza Hall Institute of Medical Research, CSL, and Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

Systemic delivery of Ag usually induces poor mucosal immunity. To improve the CD8 T cell response at mucosal sites, we targeted the Ag to MAdCAM-1, a mucosal addressin cell adhesion molecule expressed mainly by high endothelial venules (HEV) in mesenteric lymph nodes (MLN) and Peyer’s patches of gut-associated lymphoid tissue. When chemical conjugates of anti-MAdCAM-1 Ab and model Ag OVA were injected i.v., a greatly enhanced proliferative response of Ag-specific OT-I CD8 T cells was detected in MLN. This was preceded by prolonged accumulation, up to 2 wk, of the anti-MAdCAM OVA conjugate on HEV of Peyer’s patches and MLN. In contrast, nontargeted OVA conjugate was very inefficient in inducing OT-I CD8 T cell proliferation in MLN and required at least 20-fold more Ag to induce a comparable response. In addition, MAdCAM targeting elicits an endogenous OVA-specific CD8 T cell response, evident by IFN- production and target killing. Induced response offers protection against an OVA-expressing B cell lymphoma. We propose that the augmentation of gut CD8 T cell responses by MAdCAM targeting is due to both accumulation of Ag in the HEV and conversion of a soluble Ag to a cell-associated one, allowing cross-presentation by 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 work was supported by finances from the National Health and Medical Research Council of Australia, National Institutes of Health, and Juvenile Diabetes Research Foundation.

² Address correspondence and reprint requests to Dr. Andrew M. Lew, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050 Victoria, Australia. E-mail address: lew{at}wehi.edu.au

³ Abbreviations used in this paper: GALT, gut-associated lymphoid tissue; DC, dendritic cell; HEV, high endothelial venule; LN, lymph node; ILN, inguinal LN; MLN, mesenteric LN; PP, Peyer’s patch; MAdCAM, mucosal addressin cell adhesion molecule; DT, diphtheria toxin.