Dendritic cell subsets: the ultimate T cell differentiation decision makers?

It is not known whether subsets of dendritic cells provide diVerent cytokine microenvironments that determine the diVerentiation of either type-1 T helper (TH1) or TH2 cells. Human monocyte (pDC1)-derived dendritic cells (DC1) were found to induce TH1 diVerentiation, whereas dendritic cells (DC2) derived from CD4+CD3−CD11c− plasmacytoid cells (pDC2) induced TH2 diVerentiation by use of a mechanism unaVected by interleukin-4 (IL-4) or IL-12. The TH2 cytokine IL-4 enhanced DC1 maturation and killed pDC2, an eVect potentiated by IL-10 but blocked by CD40 ligand and interferon-gamma. Thus, a negative feedback loop from the mature T helper cells may selectively inhibit prolonged TH1 or TH2 responses by regulating survival of the appropriate dendritic cell subset. Comment Identifying the factors that determine Th1 versus Th2 lymphocyte diVerentiation is the goal of many scientists, and in recent years it seemed that a modicum of understanding was finally within reach. Contributions from many diVerent sources have helped to determine beyond reasonable doubt that it is the local cytokine microenvironment that plays the most important role in directing T helper cell diVerentiation during the immune response. Text books and journals are full of good examples of how Th0 cells are directed towards a Th1 phenotype by cytokines such as interleukin (IL) 12, whereas cytokines like IL-4 promote diVerentiation towards a Th2 phenotype. Furthermore, it is well accepted that the Th1 cells produce cytokines that will encourage more Th0 cells towards a Th1 diVerentiation pathway, and likewise the Th2 cells produce cytokines that direct more Th0 cells towards a Th2 diVerentiation pathway. Although these positive autocrine mechanisms make sense in the context of an ongoing immune response, the initial eVects which cause a pool of naïve T cells to be driven selectively down a particular pathway are still not well understood. A recent study by Rissoan and colleagues may have brought us one step closer to understanding this phenomenon. Rissoan et al make a very good argument that Th cell diVerentiation is controlled by specific dendritic cell (DC) subsets. The authors describe two major DC subsets— monocyte derived DC1 cells and plasmacytoid derived DC2 cells which, as their names suggest, are purported to drive Th1 and Th2 diVerentiation, respectively. These DC subsets are apparently able to drive diVerentiation of naïve Th0 cells down the Th1 or Th2 pathways independently of the cytokines that were traditionally believed to be important. DC1 cells secrete copious amounts of IL-12, thus creating a microenvironment conducive to Th1 cell diVerentiation, but the authors clearly show that DC1 cells can induce Th1 diVerentiation even in the absence of IL-12. A striking argument for Th diVerentiation being mediated by specific interactions with DC subsets and not cytokines comes from analysis of DC2 cells. DC2 cells selectively direct Th0 cells towards a Th2 phenotype, yet seem to be totally devoid of IL-4. Although the selectivity of the DC1 and DC2 subsets for driving Th1 and Th2 responses seems to be definitive, there is as yet no insight into the precise mechanism driving the diVerentiation. It will be interesting to learn whether these DC subsets mediate their activity via direct cell–cell contact or via novel soluble mediators. A fascinating twist to the story comes when the authors provide evidence of a negative feedback mechanism to maintain the balance between Th1 and Th2 responses. DC1 maturation and survival seems to be enhanced by the Th2 cytokine IL-4, whereas DC2 maturation and survival is inhibited by the Th2 cytokines IL-4 and IL-10. In fact, IL-4 and IL-10 appear to induce apoptosis of DC2 precursor cells. The authors also show that CD40L can prevent IL-4 induced killing of mature DC2 cells, presumably a safety mechanism to prevent the accidental death of a DC once it is engaged with a T cell. Interferon (IFN) ã, a Th1 cytokine, seems to promote the survival and maturation of DC2 cells. The overall result is a rather strange negative regulation which deviates away from Th1 cell development during Th1 responses and from Th2 cell development during Th2 responses. Overall, these new data provide evidence of yet another tier of control in the regulation of the homoeostatic balance between Th1 and Th2 responses. Why should gastroenterologists and mucosal immunologists be interested in DC1 and DC2 cells? Elucidating the mechanisms regulating active immunity versus tolerance in the intestine has proved to be diYcult. Quite how mucosal immune cells decide when to mount an active response to a pathogenic micro-organism while at the same time remaining tolerant to food proteins and the enteric flora is a mystery that still needs to be solved. It is probable that the selectivity of mucosal immune responsiveness is controlled by the precise nature of the antigen presenting cells in the organised gut associated lymphoid tissue. There are many DCs situated throughout all of the gut compartments, although there is little evidence that DCs in the gut are grossly diVerent to DCs elsewhere. Functionally, it is of course possible that gut DCs may behave diVerently from their peripheral counterparts, as has been shown for DCs residing in the lung. It is also feasible that DC1 and DC2 cells reside in diVerent locations within the gut itself. Perhaps one subset of DC localises beneath M cells in the dome region of Peyer’s patches, picks up antigen derived from invading pathogens and then migrates towards the Gut 1999;45:640–641 640 group.bmj.com on November 7, 2017 Published by http://gut.bmj.com/ Downloaded from