Histamine regulates cytokine production in maturing

Naive CD4+ T cells differentiate into Th1 or Th2 subsets, characterized by the release of distinct patterns of cytokines. Th1 cells produce IFN-γ and TNF-β, which promote cell-mediated immunity, while Th2 cells secrete IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, which favor humoral responses (1). The polarization of naive T cells toward Th1 or Th2 phenotypes is mediated primarily by dendritic cells (DCs). Peripheral tissues are populated by immature DCs (iDCs), highly endocytic cells that are well adapted for the capture of antigens, but are inefficient antigen-presenting cells (APCs). Upon encountering microbial products or inflammatory cytokines, iDCs reduce antigen (Ag) uptake, migrate to the draining lymph nodes, and upregulate surface expression of MHC, adhesion, and costimulatory molecules. In this mature state, DCs are potent APCs that display a unique capacity for activating and polarizing naive T cells (2–4). Although distinct DC subsets with different Th-inducing potentials have been described (5–7), DCs also display functional plasticity, and can be instructed to polarize T cells by inflammatory mediators that are present in the peripheral microenvironment. These mediators control the production of cytokines by mature DCs (mDCs) after they have migrated to the draining lymph nodes (8). For example, iDCs that are exposed in the periphery to both a maturation stimulus and IFN-γ produce high amounts of IL-12, a crucial factor in the induction of Th1 responses, when they reach the lymphoid organs (9, 10). Conversely, the presence of prostaglandin E2 or IL-10 at a site of inflammation results in mDCs that have both a reduced capacity to release IL-12 and a tendency toward Th2 polarization (11–15). The levels of DC-derived IL-12 are instrumental in the Th1–Th2 balance, but additional factors, including the strength and duration of antigenic stimulation or the nature of costimulatory molecules, might also be involved (16–19). Mast cells, the primary effectors of immediate-type allergic reactions, reside in peripheral tissues that directly interface with the external environment (20). Crosslinking of surface IgE by cognate antigens, or direct binding of microbial products or complement components to cellular receptors, induces mast cells to release large amounts of inflammatory mediators such as histamine, proteases, prostaglandins, and leukotrienes. In addition, activated mast cells produce a number of cytokines, including TNF-α, GM-CSF, IL-3, IL-4, IL-5, IL-6, IL-10, and IL-13, that have the potential to influence T cell and B cell responses; IL-4, in particular, strongly favors Th2 formation. Because mast cells have the capacity to process and present antigens to both CD4+ and CD8+ T cells in vitro, it was speculated that they might play an important role in activating and polarizing T cells in vivo (21, 22). However, this hypothesis seems unlikely, because mast cells reside in anatomical compartments that are distinct from those populated by naive T cells. On the other hand, both