A Filarial Nematode-Secreted Product Signals Dendritic Cells to Acquire a Phenotype That Drives Development of Th2 Cells

Abstract

Although exogeneous “danger” signals such as LPS can activate APC to produce a Th1 response, the nature of events initiating a Th2 response is controversial. We now show that pathogen-derived products have the capacity to induce bone marrow-derived dendritic cell cultures to acquire a phenotype that promotes the differentiation of naive CD4+ T cells toward either a Th1 or Th2 phenotype. Thus, LPS-matured dendritic cells (DC1) promote a Th1 response (increased generation of IFN-γ and reduced production of IL-4) by Ag-stimulated CD4+ T cells from the DO.11.10 transgenic mouse expressing a TCR specific for an OVA peptide (OVA323–339). In contrast, a phosphorylcholine-containing glycoprotein, ES-62, secreted by the filarial nematode, Acanthocheilonema viteae, which generates a Th2 Ab response in vivo, is found to induce the maturation of dendritic cells (DC2) with the capacity to induce Th2 responses (increased IL-4 and decreased IFN-γ). In addition, we show that the switch to either Th1 or Th2 responses is not effected by differential regulation through CD80 or CD86 and that a Th2 response is achieved in the presence of IL-12.

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

“…In addition to these indirect effects, microorganisms also directly affect sentinel DCs at the time of pathogen encounter, as has been shown previously (1)(2)(3)(4).…”

“…There is accumulating evidence that microbes drive the development of protective Th1 or Th2 cells through their effects on APCs (1)(2)(3)(4). Dendritic cells (DCs) 3 are professional APCs that are present as immature sentinel cells that efficiently sample their environment for foreign Ag at potential sites of pathogen entry. Upon activation by signals released from the microorganisms or from infected tissues, sentinel DCs undergo maturation into potent T cell stimulatory effector DCs and migrate toward the T cell areas of draining lymphoid organs.…”

CD8− Dendritic Cell Activation Status Plays an Integral Role in Influencing Th2 Response Development

“…In a recent report of the effect of another helminth Ag, Acanthocheilonema viteae ES-62, on DC function in vitro, it was shown that ES-62 plus OVA-pulsed DC primed naive DO.11.10 CD4 T cells to become Th2-like (47). This occurred in the absence of significantly increased MHC class II expression or costimulatory molecule up-regulation.…”

Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4

“…If a Th2 response, e.g., to fungal hyphae (48) or to helminthic parasites (49), occurs in the environment of a lymph node, one might expect that the resulting T cell-derived IL-4 would skew all other ongoing or beginning immune responses toward a Th2 pattern. Our data would indicate that there may be some balancing mechanism ensuring that Th1 responses are not necessarily suppressed in an IL-4-rich milieu.…”