Development of Th1-Inducing Capacity in Myeloid Dendritic Cells Requires Environmental Instruction

Abstract

Dendritic cells (DC) are key initiators of primary immune responses. Myeloid DC can secrete IL-12, a potent Th1-driving factor, and are often viewed as Th1-promoting APC. Here we show that neither a Th1- nor a Th2-inducing function is an intrinsic attribute of human myeloid DC, but both depend on environmental instruction. Uncommitted immature DC require exposure to IFN-γ, at the moment of induction of their maturation or shortly thereafter, to develop the capacity to produce high levels of IL-12p70 upon subsequent contact with naive Th cells. This effect is specific for IFN-γ and is not shared by other IL-12-inducing factors. Type 1-polarized effector DC, matured in the presence of IFN-γ, induce Th1 responses, in contrast to type 2-polarized DC matured in the presence of PGE2 that induce Th2 responses. Type 1-polarized effector DC are resistant to further modulation, which may facilitate their potential use in immunotherapy.

Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy

“…7,16 The presence of IFN-c (which can be induced by TLR ligands) during DC maturation overcomes maturation-associated DC 'exhaustion', yielding stable type 1-polarized DCs that produce higher levels of IL-12p70 and exhibit a dramatically enhanced capacity to induce Th1 responses. 26 It has been reported that IFN-c is produced by NK cells after 17 h of stimulation with poly(I:C), and it peaks at 48 h. 27 In our study, the level of IFN-c production in resting NK cells after 48 h of stimulation in the presence of TLR agonists and cytokines was higher than that observed in either activated NK cells or resting NK cells in the absence of costimulatory signals. This finding may explain why resting NK cells in the presence of stimuli induced the maturation and function of DCs more efficiently than activated NK cells.…”

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].…”

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

“…In addition, molecules derived from bacterial or viral products, as well as pro-inflammatory cytokines (TNFα and IFNγ) and T cell signals such as CD40-ligand (CD40L), can promote the secretion of IL-12p70 and TNFα from DC thereby promoting a Th1-skewed response (Schulz et al, 2000;Vieira et al, 2000). In contrast, anti-inflammatory molecules such as IL-10, prostaglandin E2 (PGE2) and corticosteroids can inhibit RTDC maturation and cytokine production and therefore promote a Th2-skewed response (Kalinski et al, 1997;Faries et al, 2001;Kalinski et al, 2001).…”