Th17 cells confer long-term adaptive immunity to oral mucosal Candida albicans infections

Abstract

Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both Th1 and Th17 responses, and considerable evidence implicates IL-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relative contribution(s) of Th1, Th17 and innate IL-17-producing cells in OPC have not been clearly defined. Here, we sought to determine the nature and function of adaptive T cell responses to OPC, using a new recall infection model. Mice subjected to infection and re-challenge with Candida mounted a robust and stable antigen specific IL-17 response in CD4+ but not CD8+ T cells. There was little evidence for Th1 or Th1/Th17 responses. The Th17 response promoted accelerated fungal clearance, and Th17 cells could confer protection in Rag1−/− mice upon adoptive transfer. Surprisingly, CD4 deficiency did not cause OPC, but was instead associated with compensatory IL-17 production by Tc17 and CD4-CD8-CD3+ cells. Therefore, classic CD4+Th17 cells protect from OPC, but can be compensated by other IL-17-producing cells in CD4-deficient hosts.

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

“…Consistent to this data, it has been also previously shown that Rag -/-mice clear the primary OPC infection without much immunopathology 27 . Under these conditions, compensatory mechanisms dependent on IL-17A producing innate immune cells have been shown to clear the infection in Rag-/-mice 17,29,30 . Taken together, although IL-17A produced by Th17 cells and neutrophil recruitment are playing a protective role at initial phases of infection, excessive production of TNF-α and other cytokines by Th17 cells, and the continued presence of neutrophils causes exacerbated immunopathology.…”

“…Although commensals such as C. albicans contribute to modulation and exacerbation of other oral inflammatory conditions, the mechanisms by which dysbiosis occur during opportunistic infections are unclear. Besides the known role of adaptive Th17 cells in memory response to C. albicans 17 , their role in initiation and perpetuation of inflammation pathology during chronic infections remain unclear. Furthermore, oral inflammatory diseases such as Sjogren's syndrome and periodontitis are associated with Th17 mediated pathology.…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…45,163,164 Th17 cells secrete numerous cytokines including IL-17A, IL-17F and IL-22, and play vital roles for immune protection against C. albicans at the majority of mucosal sites in the body. 165,166 The importance of Th17 cells in anti-Candida responses is not only portrayed by data from mice models, but also from human patients. Patients with deficiency in Th17-mediated adaptive immunity frequently suffer from chronic mucocutaneous candidiasis.…”

A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection

“…This observation suggests that the most important impact of IL-17A occurs early, whereas at later stages other factors may come into play. It should be noted, however, that IL-17RA Ϫ/Ϫ mice do not recover from candidiasis even after long-term infections (7,38), though to our knowledge, IL-17A Ϫ/Ϫ mice have not been tested in this regard. It is also possible that DAY286-IL-17A-infected mice fail to reach a threshold level of IL-17A because they are cleared rapidly during the first 4 days.…”