Is Maturation Required for Langerhans Cell Migration?

Key papers in scientific literature sometimes bring a definitive resolution to a long-awaited issue. Others may be far less decisive but importantly implore us to question the fitness of prevailing models. So it is that a paper in this issue by F. Geissmann and colleagues (1), albeit subject to some variety of interpretation, nevertheless compels us to reexamine the widely accepted idea that migration of Langerhans cells in response to inflammatory stimuli is necessarily coupled to and follows from their maturation. It is well established that in the steady-state Langerhans cells turn over very slowly, but they can be mobilized en masse by inflammatory or antigenic stimuli. In vitro and in vivo, these inflammatory mediators have also been observed to promote maturation, and Langerhans cells that migrate from skin explants in culture usually display a mature phenotype. In further agreement with the idea that migration is linked with maturation is evidence that molecules associated with migration, particularly CCR7 (2), are induced during Langerhans cell maturation (3). Dendritic cell (DC) " maturation " is defined functionally as the acquisition of potent immunogenic capacity. Among DC biologists, this term signifies a particular program of gene expression that typically includes the upregulation of CD40, CD83, CD86, MHC products, and other molecules associated with antigen presentation, along with simultaneous induction of CCR7 (4). At the same time, the ability to acquire and process antigen, a feature that characterizes immature DCs, is downregulated. Understanding the extent to which maturation and migration are coupled lies at the heart of understanding how DCs regulate T cell differentiation. If immature DCs promote naive T cells to develop a tolerogenic phenotype (5), then one is left wondering whether immature DCs traffic efficiently to lymph nodes from the periphery. If they do, then what of the belief that CCR7 is needed for DC migration to lymph nodes and that CCR7 is expressed only by mature DCs? Clearly, the fit of some pieces of the puzzle have to be reevaluated. Evidence that Immature Langerhans Cells May Accumulate in Lymph Nodes. The paper by Geissmann et al. contains two provocative observations that build on work the group had previously published (6). First, the authors present immunophenotypic analysis of human lymph node sections taken from patients that suffer from dermatopathic lymphadenopathy, a pathological disorder marked by excessive accumulation of nonproliferative Langerhans cells in lymph nodes that drain a chronically inflamed skin site (7). …