Human Dendritic Cells followingAspergillus fumigatusInfection Express the CCR7 Receptor and a Differential Pattern of Interleukin-12 (IL-12), IL-23, and IL-27 Cytokines, Which Lead to a Th1 Response

Abstract

Aspergillus fumigatus is the most prevalent airborne fungal pathogen and causes fatal invasive aspergillosis in immunocompromised patients. Given the essential role of dendritic cells (DC) in initiating and regulating immune responses, we investigated the impact of A. fumigatus conidial infection on human DC. A. fumigatus conidia were rapidly internalized and induced the release of tumor necrosis factor alpha within the first 8 h. After A. fumigatus infection, the majority of DC underwent full maturation, although CCR7 expression was observed only in DC that had internalized the conidia. Additionally, the analysis of regulatory cytokines showed that infected DC simultaneously produced interleukin-12p70 (IL-12p70) and significant amounts of IL-10. IL-10 neutralization was not able to further increase IL-12p70 production from infected DC. Whereas the central role of IL-12 in the generation of Th1 cells has long been appreciated, recently two other members of the IL-12 family, IL-23 and IL-27, were reported to play important roles in the regulation of gamma interferon (IFN-␥) production from naïve and memory T cells. A. fumigatus-infected DC were also able to express high levels of IL-23p19 and low levels of IL-27p28 at later stages of infection. According to this expression pattern, A. fumigatus-infected DC were able to prime IFN-␥ production of naïve T cells. Thus, this study on the expression of the new IL-12 family members controlling the Th1 response sheds light on a novel aspect of the contribution of DC to anti-Aspergillus immunity.

IL‐23 and the Th17 pathway promote inflammation and impair antifungal immune resistance

“…That IL-23 may serve a protective role in condition of IL-12 deficiency has already been reported in chronic cryptococcosis [36], mycobacterial infection [20] and acute pulmonary Klebsiella pneumoniae infection [7], where the protection correlated with the ability of IL-23 to activate antigen-specific IFN-c-producing CD4 + T cells, independently of IL-12p70, and to recruit PMN mediating pathogen clearance [7]. As a matter of fact, in experimental Helicobacter hepaticus-induced colitis, IL-23 has clearly been shown to drive both IFN-cand IL-17-producing cells [35].…”

“…It has already been shown that IL-23 is produced by human DC in response to Aspergillus in vitro [20]. We evaluated here whether IL-23 is produced by DC in response to C. albicans and how it relates to the production of IL-12 and IL-10, two cytokines essentially required for the induction of protective tolerance to the fungus [15].…”

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

“…IL-12 acts on naive or memory T cells and promotes the differentiation into IFN-c-producing Th1 cells. It also enhances the cytolytic activity of NK cells, thereby promoting antimicrobial defense [4,5]. IL-23 acts on memory T cells and sustains IFN-c production by these cells as well as promotes a novel T cell population (Th17) characterized by the production of IL-17A, IL-17F, TNF-a, and IL-6 [6].…”

The influence of infection early after allogeneic stem cell transplantation on the risk of leukemic relapse and graft‐versus‐host disease

“…The GVL effect is mediated by a complex network of immune cells and cytokines [1][2][3]. As inflammatory events following allogeneic SCT can change the activity of the host and donor graft immune cells that release various inflammatory cytokines [4][5][6], post-transplant infection may influence the milieu of the GVL effect and, accordingly, the risk of posttransplant leukemic relapse.…”

“…The GVL effect is mediated by a complex network of immune cells and cytokines [1][2][3]. As inflammatory events following allogeneic SCT can change the activity of the host and donor graft immune cells that release various inflammatory cytokines [4][5][6], post-transplant infection may influence the milieu of the GVL effect and, accordingly, the risk of posttransplant leukemic relapse.Post-transplant infections usually occur early after transplantation and the activation of host antigen-presenting cells and donor NK cells has been shown to occur quite early in both experimental and human allogeneic SCT [7,8]. We investigated whether a febrile infection (FI) before posttransplant day 21 was associated with a risk of leukemic relapse and graft-versus-host disease (GVHD) in patients with acute leukemia.…”