Will the Making of Plasmacytoid Dendritic Cells in Vitro Help Unravel Their Mysteries?

In this issue, two papers describe the in vitro generation of an intriguing subset of human dendritic cells (DCs), the plasmacytoid DCs (pDCs [1, 2]). For nearly 20 years after their discovery (3), DCs had to be painstakingly isolated from tissues (4). Progress was rather slow, as DCs represent a minor cell population in all tissues, and relatively few investigators appreciated their importance in antigen presentation and the control of immunity. In 1992, in vitro culture systems were identified to generate large numbers of mouse (5) and human DCs (6). These culture systems considerably accelerated the study of DCs, with many groups joining the search to unravel their mysteries (7–9). Currently , DCs are being developed in vitro from (a) bone marrow progenitors cultured in GM-CSF, with TNF being essential for human cells (6), and (b) human blood monocytes cultured with GM-CSF and IL-4 (10–12). Recently , Flt3 ligand (Flt3-L), a stromal cell product, was found to induce a massive expansion of DCs in vivo in mice (13, 14) and in humans (15, 16). Subsets of DCs. The concept of distinct DC subsets in humans came from several routes including analyses of (a) skin DCs (17), (b) DCs generated in vitro by culture of CD34 ϩ hematopoietic progenitors (HPCs [18]), and (c) blood DC precursors (19). Human skin contains two distinct subsets: Langerhans cells (LCs) within the epidermis, characterized by the expression of CD1a and Birbeck granules , and interstitial (dermal) DCs, lacking Birbeck granules but expressing coagulation factor XIIIa. These two subsets also emerge in cultures of CD34 ϩ HPCs driven by the addition of GM-CSF plus TNF-␣ (18). These subsets have common as well as unique functions (20). In particular, in-terstitial DCs, but not LCs, are able to induce the differentiation of naive B cells into immunoglobulin-secreting plasma cells. Although no unique function has yet been formally attributed to LCs, there are hints they may be particularly efficient activators of cytotoxic CD8 T cells (21, 22). Two subsets of DCs were identified in the blood, each representing a small fraction (‫ف‬ 0.3%) of the mononuclear cells (19). One subset, CD11c ϩ population, differentiated into mature DCs in response to inflammatory stimuli, whereas a second CD11c Ϫ subset was prone to prompt ap-optosis in culture, and was later identified as " pDCs. " pDCs and " DC2. " Plasmacytoid cells were first observed by experts in the histopathology of …