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Targeting Antigen to MHC Class II Molecules Promotes Efficient Cross-Presentation and Enhances Immunotherapy¹

Nina Dickgreber^*, Patrizia Stoitzner^*, Yan Bai^*, Kylie M. Price^*, Kathryn J. Farrand^*, Kristy Manning^,, Catherine E. Angel^,, P. Rod Dunbar^,, Franca Ronchese^*, John D. Fraser^,, B. Thomas Bäckström^* and Ian F. Hermans^2,*

^* Malaghan Institute of Medical Research, Wellington, and School of Medical Sciences, School of Biological Sciences, Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand

An efficient pathway of cross-presentation common to a range of dendritic cell (DC) populations was identified by targeting Ag to MHC class II molecules. This finding was achieved by conjugating Ag to M1, which is a modified version of the superantigen streptococcal mitogenic exotoxin Z-2 that binds to MHC class II molecules but cannot directly stimulate T cells. M1 conjugates were efficiently presented to CD4⁺ and CD8⁺ T cells by bone marrow-derived DC and Langerhans cells in vitro. Whereas nonconjugated Ag was preferentially cross-presented by splenic CD8⁺ DC in vivo, M1-conjugated Ag was cross-presented by all dendritic subtypes assessed. Potent effector T cell responses with antitumor activity were elicited when M1 conjugates were injected together with an adjuvant. This method of Ag delivery has significant potential in therapeutic applications.

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 the New Zealand Health Research Council, the Cancer Society of New Zealand, the Wellington Medical Research Foundation, and the Genesis Oncology Trust. P.S. was supported by the Erwin Schroedinger Auslandsstipendium Grant FWF-J2479 from the Austrian Science Fund. I.F.H. was supported by a New Zealand Health Research Council Sir Charles Hercus Fellowship.

² Address correspondence and reprint requests to Dr. Ian F. Hermans, Malaghan Institute of Medical Research, PO Box 7060, Wellington 6242, New Zealand. E-mail address: ihermans{at}malaghan.org.nz

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; LC, Langerhans cell; -GalCer, -galactosylceramide; iNKT, invariant NKT; SMEZ, streptococcal mitogenic exotoxin Z; Cyt c, cytochrome c; EEA, early endosomal Ag.