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Dendritic Cells Require the NF-B2 Pathway for Cross-Presentation of Soluble Antigens¹

Evan F. Lind^*, Cory L. Ahonen^*, Anna Wasiuk^*, Yoko Kosaka^*, Burkhard Becher, Kathy A. Bennett^* and Randolph J. Noelle^2,*

^* Department of Microbiology and Immunology, Dartmouth Medical School and the Norris Cotton Cancer Center, Lebanon, NH 03756; and Department of Neurology, Neuroimmunology Unit, University of Zurich, Zurich, Switzerland

NF-B-inducing kinase (NIK) is responsible for activation of the non-canonical p100 processing pathway of NF-B activation. This kinase has been shown to be critical for activation of this pathway after signaling through several TNF family members including CD40. The functional importance of this pathway in CD40 and TLR-induced dendritic cell (DC) differentiation was studied in vivo in the alymphoplasia (Aly) mouse. The Aly mouse expresses a mutant NIK molecule that prohibits the induction of the non-canonical pathway. We show that while MHC class II presentation and in vivo migration of Aly DCs is intact, these cells are unable to cross-prime CD8⁺ T cells to exogenous Ag. Gene expression array analysis of DCs matured in vivo indicates multiple defects in Ag processing pathways after maturation and provide a global view of the genes that are regulated by the NF-B2 pathway in DCs. These experiments indicate a possible role for NIK in mediating cross-priming of soluble Ag. In addition, our findings explain the profound immune unresponsiveness of the Aly mouse.

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 National Institutes of Health Grant CA09143 to R.N.

² Address correspondence and reprint requests to Dr. Randolph J. Noelle, Department of Microbiology and Immunology, Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756. E-mail address: rjn{at}dartmouth.edu

³ Abbreviations used in this paper: DC, dendritic cell; NIK, NF-B-inducing kinase; Aly, alymphoplasia.

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