Interleukin-23 (IL-23)-IL-17 Cytokine Axis in Murine Pneumocystis carinii Infection

Abstract

Host defense mechanisms against Pneumocystis carinii are not fully understood. Previous work in the murine model has shown that host defense against infection is critically dependent upon host CD4 ؉ T cells. The recently described Th17 immune response is predominantly a function of effector CD4 ؉ T cells stimulated by interleukin-23 (IL-23), but whether these cells are required for defense against P. carinii infection is unknown. We tested the hypothesis that P. carinii stimulates the early release of IL-23, leading to increases in IL-17 production and lung effector CD4 ؉ T-cell population that mediate clearance of infection. In vitro, stimulation of alveolar macrophages with P. carinii induced IL-23, and IL-23p19 mRNA was expressed in lungs of mice infected with this pathogen. To address the role of IL-23 in resistance to P. carinii, IL-23p19؊/؊ and wild-type control C57BL/6 mice were infected and their fungal burdens and cytokine/chemokine responses were compared. IL-23p19؊/؊ mice displayed transient but impaired clearance of infection, which was most apparent 2 weeks after inoculation. In confirmatory studies, the administration of either anti-IL-23p19 or anti-IL-17 neutralizing antibody to wild-type mice infected with P. carinii also caused increases in fungal burdens. IL-17 and the lymphocyte chemokines IP-10, MIG, MIP-1␣, MIP-1␤, and RANTES were decreased in the lungs of infected IL-23p19؊/؊ mice in comparison to their levels in the lungs of wild-type mice. In IL-23p19؊/؊ mice infected with P. carinii, there were fewer effector CD4 ؉ T cells in the lung tissue. Collectively, these studies indicate that the IL-23-IL-17 axis participates in host defense against P. carinii.

Interleukin‐17 as an Effector Molecule of Innate and Acquired Immunity against Infections

“…Pulmonary Pneumocystis carinii infection also induced IL-23 and IL-17, and protection against the fungi depended on both IL-23 and IL-17 (32). Since IL-23/IL-17 axis participated in protective acquired immunity against the all three fungal infections, Th17 would be important in protective response against fungal infections.…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…65 Th17 cells also have an increasingly recognized role in the adaptive immune response to a variety of fungal pathogens. 66,67 Chamilos et al found that exposure of the b-glucan component of the cell wall of a mutant strain of H. capsulatum decreased its pathogenicity and stimulated an increased production of IL-23 by DCs and a resultant Th17 antifungal response. 68 This was found using a mutant strain of H. capsulatum that is unable to generate a-glucan, thereby exposing b-glucan to DCs.…”

IP-10 release assays in the diagnosis of tuberculosis infection: current status and future directions

“…However, comparisons of indeterm inate results are difficult to make due to the lack of a validated cutoff for an indeterminate IP-10 response (see below). The immunological mechanisms underlying these suggested differences between IFN-g and IP-10 in HIV-infected patients are as yet unknown, but are probably due to a combination of both the higher magnitude of response and the broader induction profile of IP-10 compared with IFN-g [37][38][39][40][41][42][43][44][45][46]. Sutherland and colleagues recently demonstrated that coincident with the loss of total CD4 count, the TB antigen-specific immune response changed from a polyfunctional CD4 response to a monofunctional IFN-g or TNF-a CD8 T-cell response [74].…”

“…IP-10 secretion appears to be driven by multiple signals, mainly T-cell-derived IFN-g, but also IL-2, IFN-a, IFN-b, IL-27, IL-17, IL-23, and autocrine APC-derived TNF-a and IL-1b. TNF-a is a weak IP-10 inducer per se, but a potent synergistic inducer when acting with the interferons [37][38][39][40][41][42][43][44][45][46]. Because of the many different pathways that can lead to IP-10 secretion, IP-10 can be considered a downstream marker to typical readout markers in CMI assays, such as IL-2 and IFN-g [47,48].…”