Cutting edge: Resistance to apoptosis and continuous proliferation of dendritic cells deficient for TNF receptor-1

The individual roles of the two TNFRs on dendritic cells (DC) are poorly un derstood. Investigating bone marrow-derived DC from TNFR-deficient mice, we found that cultures from TNFR1(-/-) mice continue to form proliferating cl usters for 6-9 mo. In contrast, DC derived from wild-type, TNFR2(-/-), or T NFR1/2(-/-) mice survived for only 3-4 wk. DC obtained from these TNFR1(-/- ) long term cultures (LTC) mice show an unusual mixed immature/mature pheno type. The continuous proliferation of the LTC is GM-CSF dependent and corre lates with decreased protein levels of the cyclin-dependent kinase inhibito rs p27(KIP1) and p21(CIP1), Prolonged survival of TNFR1(-/-) DC appears to he independent from NF-kappaB and Bcl-2 pathways and is rather enabled by t he down-regulation of CD95, resulting in the resistance to CD95 Ligand-indu ced apoptosis, These data point to proapoptotic signals mediated via TNFR1 and antiapoptotic signals mediated via TNFR2(-/-) in DC.