Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals

Abstract

Upon microbial infection, specific Th1 or Th2 responses develop depending on the type of microbe. Here, we demonstrate that different microbial compounds polarize the maturation of human myeloid dendritic cells (DCs) into stably committed Th1 cell-promoting (DC1) or Th2 cell-promoting (DC2) effector DCs that polarize Th cells via different mechanisms. Protein extract derived from the helminth Schistosoma mansoni induced the development of DC2s that promote the development of Th2 cells via the enhanced expression of OX40 ligand. Likewise, toxin from the extracellular bacterium Vibrio cholerae induced development of DC2s as well, however, via an OX40 ligand-independent, still unknown mechanism. In contrast, toxin from the intracellular bacterium Bordetella pertussis induced the development of DC1s with enhanced IL-12 production, which promotes a Th1 cell development. Poly(I:C) (dsRNA, mimic for virus) induced the development of extremely potent Th1-inducing DC1, surprisingly, without an enhanced IL-12 production. The obtained DC1s and DC2s are genuine effector cells that stably express Th cell-polarizing factors and are unresponsive to further modulation. The data suggest that the molecular basis of Th1/Th2 polarization via DCs is unexpectedly diverse and is adapted to the nature of the microbial compounds.

Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering

“…Similarly, murine bone marrow-derived DC treated with LPS or Gram-negative bacteria preferentially prime Th1 responses while cells exposed to certain worm products direct Th2 development (34,45). In the human system, pathogen products have also been shown to dictate the cytokine producing and Th-skewing capacity of monocyte-derived DC (46). Even socalled DC2 plasmacytoid cells can make IL-12 in response to CpG DNA plus CD40L (9) and can prime Th1 responses after exposure to viruses (47,48), arguing that their Th2-directing ability is not hardwired.…”

Cholera Toxin Promotes the Induction of Regulatory T Cells Specific for Bystander Antigens by Modulating Dendritic Cell Activation

“…DC have a major influence on the priming of naive T cells, and it has been suggested that plasmacytoid and myeloid DC promote Th1 and Th2 cells, respectively (27), whereas immature DC have been implicated in driving anergic or Tr cells (28). Alternatively, the same subtype of DC may selectively enhance the development of distinct T cell subtypes depending on the dose and type of Ag or immunomodulatory molecules and the environment pertaining at the time of maturation (2,10,29). Our data suggest that DC activated with CT promote the induction of IL-10-secreting T cells, but not Th1 cells.…”

“…Our data demonstrate that T cells generated with CT as an adjuvant secrete high levels of IL-10 and are capable of suppressing IFN-␥ production by Th1 cells and therefore fulfill the primary criteria for designation as Tr cells. Furthermore, the adoptive transfer experiments suggest that CT-modulated DC that direct the induction of IL-10-secreting T cells have a distinct phenotype from CpG-ODNor LPS-stimulated DC, which drive Th1 cells (9,10).…”

“…Certain TLR ligands, including CpG motif-containing oligonucleotides (CpG-ODN), LPS and poly(I: C), stimulate IL-12 production by DC and macrophages and promote the induction of Th1 cells (9,10). In contrast, filamentous hemagglutinin from Bordetella pertussis enhances IL-10 production from macrophages and DC and promotes the induction of Tr1 cells (4).…”

Roles of toll-like receptors in natural interferon-producing cells as sensors in immune surveillance

“…Most myeloid DCs have some capacity to produce IL-12 and, thereby, to induce Th1 development. However, this capacity varies with the conditions of their maturational stage or stimulation delivered to DCs [43][44][45][46][47][48]. A similar functional plasticity is observed in IPC-derived DCs [8, 49 -51].…”