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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1540-1549.
Prepublished online as a Blood First Edition Paper on May 4, 2007; DOI 10.1182/blood-2006-11-056010.
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IMMUNOBIOLOGY
Noncanonical NF- B signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation
Sander W. Tas1,
Margriet J. Vervoordeldonk1,
Najat Hajji1,
Joost H. N. Schuitemaker2,
Koen F. van der Sluijs3,
Michael J. May4,
Sankar Ghosh5,
Martien L. Kapsenberg2,
Paul P. Tak1, and
Esther C. de Jong2
1 Division of Clinical Immunology and Rheumatology,
2 Department of Cell Biology and Histology, and
3 Department of Experimental Immunology, Academic Medical Center (AMC)/University of Amsterdam, Amsterdam, the Netherlands;
4 School of Veterinary Medicine, Department of Animal Biology, University of Pennsylvania, Philadelphia;
5 Immunobiology Section, Yale University Medical School, New Haven, CT
Ligation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF- B signaling, as well as late expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-B pathway using the NEMO-binding domain peptide or the noncanonical NF-B pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-B signaling. Also, noncanonical NF-B signaling down-regulates proinflammatory cytokine production in DCs. In addition, selective activation of the noncanonical NF-B pathway results in noninflammatory DCs that suppress T-cell activation and promote the development of T cells with regulatory properties. These findings reveal an important role of the noncanonical NF-B pathway in the regulation of immunity.
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