While dendritic cells (DCs) are best known for their capacity to initiate specific immune responses, more recent findings show that DCs are essential in controlling not only central but also peripheral tolerance, and that they are closely linked to innate immunity. Such distinct functions can only be accomplished by adaptive flexibility and diversification. Indeed, multiple subsets of immature and mature dendritic cells, distinguishable by surface antigen expression, localization, and cytokine production, have been described.

One such subset, consisting of the plasmacytoid dendritic cell (DC2) and its immediate precursor, the plasmacytoid cell (pDC2, or pre-DC2), was recently characterized in humans. Upon stimulation, pDC2s produce high amounts of IFN-α/β and can differentiate in vitro into DC2s that are capable of inducing strong T-helper cell (Th) responses (reviewed in Liu, Cell. 2001;106:259-262). Subsequent studies showed that pDC2s are mobilized by G-CSF and Flt3 ligand, and that high numbers in peripheral blood or marrow grafts potentially limit graft-versus-host disease and are associated with increased relapse rates after allogeneic transplantation. PDC2s are susceptible to HIV infection, and their depletion correlates with disease progression and the occurrence of opportunistic infections. Accumulation of pDC2/DC2s in allergic and automimmune lesions was reported, suggesting functional involvement in these immunologic “hot spots.” However, definitive studies have not been available due to the lack of suitable models.

Björck (page 3520) and Nakano and colleagues (J Exp Med. 2001;194:1171-1178) have now identified a murine cell population resembling the human pDC2/DC2s. These cells possess key pDC2 features including the production of high amounts of IFN-α upon viral challenge and the differentiation into mature DCs upon IL-3R/CD40 stimulation in vitro. In contrast to their human counterparts, the murine cells express CD11c, and they can produce IL-12, which is still controversial in human DC2s. Other analogies to human plasmacytoid DCs regarding Th responses, pattern recognition, and chemokine receptor expression need to be explored. But irrespective of likely minor differences, the characterization of murine plasmacytoid DCs provides the means to rigorously study this cell type. Specifically, it will be possible to elucidate their lineage origin and developmental pathways and, more importantly, to clarify their function in immunologic challenges such as infection, autoimmune disease, cancer, and transplantation.