Parasite-Induced Th2 Polarization Is Associated with Down-Regulated Dendritic Cell Responsiveness to Th1 Stimuli and a Transient Delay in T Lymphocyte Cycling

Abstract

The nature of the signals that bias Th effector choice is still not completely understood. Using parasite extracts from pathogens known to induce polarized Th1 or Th2 responses and an in vitro experimental model for priming murine CD4+ cells, we demonstrated that splenic dendritic cells (DC), but not B cells, promote Th1/Th2 differentiation of naive CD4+ lymphocytes. Th polarization in this system was found not to depend on DC secretion of the polarizing cytokines IL-12/IL-4, but instead correlated with distinct states of DC activation induced by the different parasite preparations. As expected, conditioning of DC for Th1 development was associated with up-regulation of costimulatory molecules and enhanced chemokine production and required intact MyD88 signaling. In contrast, conditioning of DC for Th2 differentiation correlated with down-regulation of many of the same functions and was MyD88 independent. This dampened DC activation was accompanied in the cocultures by a reduction in the frequency of CD4+ lymphocytes exiting the first division of the cell cycle. When the latter was mimicked by drug-induced arrest of peptide-primed CD4+ cells after the S phase of the first cycle, a marked Th2 polarization was also observed. Together, these findings suggest that the emergence of IL-4-producing CD4+ lymphocytes results from a suppression in DC function leading to a temporary delay in initial T cell cycling.

T‐helper 1 and T‐helper 2 adjuvants induce distinct differences in the magnitude, quality and kinetics of the early inflammatory response at the site of injection

“…More recently, the same group has found that parasite-induced Th2 responses are related to a dampening of Th1-stimulating immune reactions and a lack of MyD88-signalling. 55 In addition, Sun et al 56,57 have found that Th2 responses arise when Th1 or TLR signals are lacking and, although it has been demonstrated that if IL-4 is blocked following immunization with aluminium a Th1-like response arises, 58 Th2 responses can still be found in the absence of IL-4 or IL-4 signalling in vivo. 26,27 Our microarray experiment, which was based on individual mice, indicates that the initial immune response to Al(OH) 3 is more delayed compared with that of DDA/MPL because metabolic processes (e.g.…”

Dendritic Cell-Intrinsic Expression of NF-κB1 Is Required to Promote Optimal Th2 Cell Differentiation

“…Consistent with this model, possible functions of NF-B-dependent MAPK activation in Schistosome Ag-conditioned DC include the induction of factors that would suppress proinflammatory signals (12,22,26) and allow instruction of Th2 cell differentiation. Alternatively, these factors may control proliferative arrest of CD4 ϩ T cells, another pathway that has been proposed to influence Th2 cell differentiation (21).…”

“…Schistosome eggs are potent inducers of Th2 responses and in previous studies SEA-pulsed WT DC, although showing minimal up-regulation of classical activation markers were able to prime for Th2 cytokine production (17,20,21). Although no significant differences in expression of MHC class II, CD80, CD86, or CD40 were observed between SEA-pulsed WT and NF-B1 Ϫ/Ϫ DC (data not shown), the ability of NF-B1 Ϫ/Ϫ DC to prime for IL-4 and IL-5 production was lower than WT counterparts (Fig.…”

“…Th cell differentiation is closely linked to proliferation and a recent study demonstrated that Th2 cell differentiation was associated with DC-controlled proliferative arrest of CD4 ϩ T cells (21). To determine whether impaired Th2 cytokine responses in NF-B1 Ϫ/Ϫ mice were associated with defects in T cell activation or proliferation, an in vitro Th cell differentiation assay was adopted.…”

“…Schistosome eggs are a potent natural Th2 cyokine-inducing stimulus and provide a welldefined in vivo model of type 2 inflammation. Furthermore, SEApulsed DC can prime for Th2 cytokine responses following adoptive transfer into naive mice, providing a model to dissect cellintrinsic regulatory pathways that influence Th2 cytokine responses (17,20,21). To investigate whether NF-B1 regulates Th2 cytokine responses in this model, Schistosome eggs were injected s.c. into WT and NF-B1 Ϫ/Ϫ mice, and cytokine production in the draining popliteal LN was determined 7 days later.…”