Graphical Abstract Highlights d The skin commensal yeast Malassezia drives type 17 immunity in the skin d Malassezia-specific human memory T cells display a Th17 phenotype d Mice deficient in IL-17AF or IL-23 show uncontrolled Malassezia growth on the skin d In the disrupted skin, IL-23 and IL-17AF promote Malasseziainduced inflammation SUMMARY Commensal fungi of the mammalian skin, such as those of the genus Malassezia, are associated with atopic dermatitis and other common inflammatory skin disorders. Understanding of the causative relationship between fungal commensalism and disease manifestation remains incomplete. By developing a murine epicutaneous infection model, we found Malassezia spp. selectively induce IL-17 and related cytokines.This response is key in preventing fungal overgrowth on the skin, as disruption of the IL-23-IL-17 axis compromises Malassezia-specific cutaneous immunity. Under conditions of impaired skin integrity, mimicking a hallmark of atopic dermatitis, the presence of Malassezia dramatically aggravates cutaneous inflammation, which again was IL-23 and IL-17 dependent. Consistently, we found a CCR6 + Th17 subset of memory T cells to be Malassezia specific in both healthy individuals and atopic dermatitis patients, whereby the latter showed enhanced frequency of these cells. Thus, the Malassezia-induced type 17 response is pivotal in orchestrating antifungal immunity and in actively promoting skin inflammation.

The host immune status is critical for preventing opportunistic infections with Candida albicans. Whether the natural fungal diversity that exists between C. albicans isolates also influences disease development remains unclear. Here, we used an experimental model of oral infection to probe the host response to diverse C. albicans isolates in vivo and found dramatic differences in their ability to persist in the oral mucosa, which inversely correlated with the degree and kinetics of immune activation in the host. Strikingly, the requirement of interleukin (IL)-17 signaling for fungal control was conserved between isolates, including isolates with delayed induction of IL-17. This underscores the relevance of IL-17 immunity in mucosal defense against C. albicans. In contrast, the accumulation of neutrophils and induction of inflammation in the infected tissue was strictly strain dependent. The dichotomy of the inflammatory neutrophil response was linked to the capacity of fungal strains to cause cellular damage and release of alarmins from the epithelium. The epithelium thus translates differences in the fungus into qualitatively distinct host responses. Altogether, this study provides a comprehensive understanding of the antifungal response in the oral mucosa and demonstrates the relevance of evaluating intraspecies differences for the outcome of fungal-host interactions in vivo.

Mucosal infections with Candida albicans belong to the most frequent forms of fungal diseases. Host protection is conferred by cellular immunity; however, the induction of antifungal immunity is not well understood. Using a mouse model of oropharyngeal candidiasis (OPC) we show that interleukin-1 receptor (IL-1R) signaling is critical for fungal control at the onset of infection through its impact on neutrophils at two levels. We demonstrate that both the recruitment of circulating neutrophils to the site of infection and the mobilization of newly generated neutrophils from the bone marrow depended on IL-1R. Consistently, IL-1R-deficient mice displayed impaired chemokine production at the site of infection and defective secretion of granulocyte colony-stimulating factor (G-CSF) in the circulation in response to C. albicans. Strikingly, endothelial cells were identified as the primary cellular source of G-CSF during OPC, which responded to IL-1α that was released from keratinocytes in the infected tissue. The IL-1-dependent crosstalk between two different cellular subsets of the nonhematopoietic compartment was confirmed in vitro using a novel murine tongue-derived keratinocyte cell line and an established endothelial cell line. These data establish a new link between IL-1 and granulopoiesis in the context of fungal infection. Together, we identified two complementary mechanisms coordinating the neutrophil response in the oral mucosa, which is critical for preventing fungal growth and dissemination, and thus protects the host from disease.

Vaccinations in medicine are typically administered into the muscle beneath the skin or into the subcutaneous fat. As a consequence, the vaccine is immunologically processed by antigenpresenting cells of the skin or the muscle. Recent evidence suggests that the clinically seldom used intradermal route is effective and possibly even superior to the conventional subcutaneous or intramuscular route. Several types of professional antigen-presenting cells inhabit the healthy skin. Epidermal Langerhans cells (CD207/langerin + ), dermal langerin neg , and dermal langerin + dendritic cells (DC) have been described, the latter subset so far only in mouse skin. In human skin langerin neg dermal DC can be further classified based on their reciprocal expression of CD1a and CD14. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Yet, specializations of these different populations have become apparent. Langerhans cells in human skin appear to be specialized for induction of cytotoxic T lymphocytes; human CD14 + dermal DC can promote antibody production by B cells. It is currently attempted to rationally devise and improve vaccines by harnessing such specific properties of skin DC. This © Springer-Verlag Berlin Heidelberg 2011 nikolaus.romani@i-med.ac.at. Europe PMC Funders GroupAuthor Manuscript Curr Top Microbiol Immunol. Author manuscript; available in PMC 2015 January 07. Published in final edited form as:Curr Top Microbiol Immunol. 2012 ; 351: 113-138. doi:10.1007/82_2010_118. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts could be achieved by specifically targeting functionally diverse skin DC subsets. We discuss here advances in our knowledge on the immunological properties of skin DC and strategies to significantly improve the outcome of vaccinations by applying this knowledge. Modern Vaccine Science-Devising Rational VaccinesVaccinations in medicine are a success story. They are well established and well investigated. The traditional vaccines induce robust immunity against bacterial and viral microbes, thereby preventing the outbreak of infectious diseases. The commonly applied vaccines, which are used worldwide, were developed by microbiologists. Louis Pasteur discovered that distinct microbes cause diseases and that attenuated microbes can induce long-lived protection against a subsequent infection by the pathogenic, i.e., non-attenuated form of that organism. This was long before there was any clear understanding of cellular, let alone molecular mechanisms of vaccine immunity, such as the decisive role that dendritic cells (DC) have in this process (Steinman 2008b). The twentieth century brought major advances in our knowledge and understanding of the immune system. This initiated a new period of vaccine research that is based on our understanding and exploitation of key immune principles rather than on the empirical approach. A vaccine can be defined as a formulation that induces specific, non-toxic, and long-lasting immune...

Key Points DC-specific ablation of p14 leads to the disruption of the LC network in situ by inducing apoptosis and proliferation deficiency in LCs. p14 deficiency affects ERK/mTOR signaling in DCs and results in transient recruitment of circulation-derived short-term LCs to the skin.