Cycling of human dendritic cell effector phenotypes in response to TNF-alpha: modification of the current 'maturation' paradigm and implications for in vivo immunoregulation

Dendritic cells (DCs) are potent antigen presenting cells reported to under go irreversible functional 'maturation' in response to inflammatory signals such as TNF-alpha. The current paradigm holds that this DC maturation even t is required for full functional capacity and represents terminal differen tiation of this cell type, culminating in apoptotic cell death. This provid es a possible mechanism for avoiding dysregulated immunostimulatory activit y, but imposes constraints on the capacity of DCs to influence subsequent i mmune responses and to participate in immunological memory. We report that the cell surface and functional effects induced by TNF-alpha are reversible and reinducible. These effects are accompanied by a concordant modulation of cytokine mRNA expression that includes the induction of proinflammatory factors (IL-15, IL-12, LT-a!, LT-beta, TNF-alpha, RANTES) which is coincide nt with the down-regulation of counter-regulatory cytokines (IL-10, TGF-bet a 1, TGF-beta 2, IL-1 RA, MCP-1). The resultant net effect is a dendritic c ell activation state characterized by a transient proinflammatory posture. These results demonstrate that 1) human DCs do not undergo terminal 'matura tion' in response to TNF-alpha, 2) DC phenotypes are more pleiotropic than previously thought, and 3) DCs are potential immunoregulatory effector cell s with implications for control of immune responses in both in vivo and in vitro systems.-Nelson, E. L., Strobl, S., Subleski, J., Prieto, D., Kopp, W . C., Nelson, P. J. Cycling of human dendritic cell effector phenotypes in response to TNF-alpha: modification of the current 'maturation' paradigm an d implications for in vivo immunoregulation. Cycling of human dendritic cel l effector phenotypes in response to TNF-alpha modification of the current 'maturation' paradigm and implications for in vivo immunoregulation.