THE ROLE OF IL-17 IN THE INNATE IMMUNE RESPONSE TO OROPHARYNGEAL CANDIDIASIS

Oropharyngeal candidiasis (OPC; thrush) is an opportunistic oral infection caused by the commensal fungus Candida albicans that afflicts immunosuppressed and immunocompromised individuals. Although patients with HIV/AIDS are the prototypical population associated with development of thrush, there are a host of conditions that lead to susceptibility to OPC, including Hyper-IgE Syndrome (HIES). The autosomal dominant form of HIES (AD-HIES) is characterized by inherited dominant negative mutations in the STAT3 transcription factor, which is crucial for physiologic homeostasis and development in many tissues, including immune cells. Due to the ubiquitous nature of STAT3, mutations in this gene lead to a highly varied set of clinical sequelae, including oral thrush. Numerous cytokines utilize STAT3 to mediate downstream signaling, including IL-6 and IL-23, which are crucial for the differentiation and expansion of T helper 17 (Th17) cells, respectively. IL-23 is necessary for 1) in vivo expansion of Th17 cells, and 2) the secretion of IL-17 and other proinflammatory cytokines. Recently, the Th17 lineage has been shown to play a major role in host defense against OPC. Our lab has previously shown that mice deficient in the IL-17 receptor (IL-17RAKO) and IL-23p19 (IL-23KO) are susceptible to OPC. Furthermore, saliva from both AD-HIES patients and IL-23KO mice exhibits reduced ability to kill C. albicans ex vivo. However, despite the requirement for both IL-17 and IL-23 in protecting against OPC, we found that CD4-specific STAT3 knockout (CD4(stat3KO)) mice are not susceptible to our model of OPC. These data suggested that STAT3 mediates the initial response to oral C. albicans challenge by inducing an IL-17-producing subset other than Th17. Experiments carried out in this study revealed that the initial source of IL-17 is lymphocytic, and is likely multifactorial, involving both γδ and αβ T cells. Furthermore, in this study, natural killer and natural killer T cells were shown to have no apparent role in IL-17 secretion in response to C. albicans challenge in the oral cavity. In addition, while a memory or rechallenge response may involve CD4+ Th17 cells, this lineage appears to be unessential for the initial response to C. albicans in the oral cavity. Although we also attempted to examine the immune response to OPC using a mouse model of HIES harboring a transgenic STAT3 mutation, these mice proved resistant to C. albicans challenge at the buccal mucosa. However, despite the OPC resistance, they did exhibit a skin phenotype consistent with STAT3 deficiency, including eczematous lesions and delayed wound healing. These findings suggest that this mouse model may be used to study the role of STAT3 in both eczema as well as the immune response to cutaneous Staphylococcus aureus and C. albicans skin infections in the context of STAT3