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Cutting Edge: Resistance to Apoptosis and Continuous Proliferation of Dendritic Cells Deficient for TNF Receptor-1¹

Jens Oliver Funk^*, Henning Walczak, Constanze Voigtländer^*, Susanne Berchtold^*, Thomas Baumeister^*, Pia Rauch^*, Susanne Rössner^*, Alexander Steinkasserer^*, Gerold Schuler^* and Manfred B. Lutz^2,*

^* Department of Dermatology, University of Erlangen, Erlangen, Germany; and Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany

The individual roles of the two TNFRs on dendritic cells (DC) are poorly understood. Investigating bone marrow-derived DC from TNFR-deficient mice, we found that cultures from TNFR1^-/- mice continue to form proliferating clusters for 6–9 mo. In contrast, DC derived from wild-type, TNFR2^-/-, or TNFR1/2^-/- mice survived for only 3–4 wk. DC obtained from these TNFR1^-/- long term cultures (LTC) mice show an unusual mixed immature/mature phenotype. The continuous proliferation of the LTC is GM-CSF dependent and correlates with decreased protein levels of the cyclin-dependent kinase inhibitors p27^KIP1 and p21^CIP1. Prolonged survival of TNFR1^-/- DC appears to be independent from NF-B and Bcl-2 pathways and is rather enabled by the down-regulation of CD95, resulting in the resistance to CD95 ligand-induced apoptosis. These data point to proapoptotic signals mediated via TNFR1 and antiapoptotic signals mediated via TNFR2 in DC.

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