Interleukin-12 p40 Secretion by Cutaneous CD11c⁺and F4/80⁺Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity toSchistosomamansoni

Abstract

Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1␣ and interleukin-1␤ (IL-1␤) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10 ؊/؊ mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40 ؉ cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia ؉ , consistent with their being antigen-presenting cells. Labeling of IL-12 ؉ cells for CD11c, CD205, CD8␣, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c ؊ F4/80 ؉ , suggesting that macrophages were an additional source of IL-12 in the skin.The processes leading to the induction of polarized T-helper lymphocyte populations following exposure of the host to infectious pathogens are believed to involve interactions between the innate and acquired immune systems at the initial site of infection (24). In this context, the skin is a major barrier across which many infectious agents, including the parasitic helminth Schistosoma mansoni, gain entry to the host. This site is populated by an array of immune-competent accessory cells acting as sentinels, which are an important source of cytokines and chemokines responsible for amplifying the inflammatory response by activating resident cells and recruiting additional cells (9, 49). Cytokines also have an important influence on Th cell development, with interleukin-12 (IL-12), IL-18, tumor necrosis factor alpha, and IL-1␤ being key factors in the differentiation of Th1 cells (20,29).In our study, we examined innate immune responses elicited in the skin of mice exposed to radiation-attenuated (RA) larvae of S. mansoni. In this vaccine model, RA larvae induce Th1-type acquired immunity, which is characterized by the persistence of gamma interferon (IFN-␥)-secreting Th cells in the skin-draining lymph nodes (sdLN) (26) and confers 60 to 70% protection against a challenge infection (11). There is clear evidence that IL-12 is a critical component of this Th1-mediated protection (2, 47). In contrast,...

Fluorescent Imaging of Antigen Released by a Skin-Invading Helminth Reveals Differential Uptake and Activation Profiles by Antigen Presenting Cells

“…Neutrophils are an important source of chemokines which attract monocytes, MΦ and DC to the site of infection [52]. Indeed CCL3 and CCL4 are present at increased levels immediately after cercarial penetration [7]. The decline in CFDA-SE + neutrophils after 24 hrs is likely to reflect rapid degradation of labelled ES material due to their potent proteolytic activity [53] followed by their rapid clearance from the skin; none were observed in the sdLN.…”

ICAM-1 expression in adipose tissue: effects of diet-induced obesity in mice

“…CD14, another commonly used marker for monocytes and macrophages, binds bacterial LPS and is expressed on cells of monocytic lineage and is downregulated on cells that develop into mature myeloid dendritic cells (34,52). CD11c is often considered a hallmark of dendritic cells (8), however, several reports have shown that some macro-phage subsets can also express CD11c (20,31). Using this panel of markers, we have identified for the first time increases in CD11c-positive macrophages in adipose tissue, in response to a high-fat diet.…”

Impaired immune response to vaccinia virus inoculated at the site of cutaneous allergic inflammation

“…This finding suggests that local factors in OVA-sensitized skin promote the expression of IFN-g. A potential candidate is increased numbers of myeloid DCs, which are a potent source of IL-12. 32 The impaired T H 1 response of mice inoculated with VV at sites of allergic skin inflammation was associated with the appearance of satellite pox lesions (Fig 1, B and C). However, these mice exhibited neither weight loss nor increased viral loads in skin or internal organs examined.…”