Th1 and Th17 Immune Responses Act Complementarily to Optimally Control Superficial Dermatophytosis

Abstract

Dermatophytoses are among the most common fungal infections worldwide but little is known about the immune response in them. By comparing Trichophyton benhamiae acute superficial dermatophytosis in WT and Rag2 mice, we showed that TCR-mediated immunity is critical for fungal clearance and clinical recovery. In WT mice, CD4+ T-cells isolated from the skin-draining lymph nodes exhibit both Th1 and Th17 differentiation during infection, with regard to produced cytokines or mRNA levels of transcription factors. Using IL-17A- and IFN-γ-deficient mice, we showed that IL-17A and IFN-γ are individually dispensable, but together contribute to the optimal resolution of dermatophytosis. Furthermore, we generated and infected IL-17A and IFN-γ double-deficient mice and showed that both fungal clearance and clinical recovery were much lower in these mice than in single-deficient mice, suggestive of the complementary roles of the two cytokines in dermatophytosis resolution. Thus, our data suggest that TCR-mediated immunity is critical for the optimal control of superficial dermatophytosis and that adaptive immunity is polarized to both Th1 and Th17 responses, with the Th17 antifungal response acting on dermatophyte clearance and the Th1 one being involved in both fungal clearance and Th17-inflammation down-modulation.

Interleukin-17 in Antifungal Immunity

“…A similar protective role for Th17 has been demonstrated against the dermatophyte Trichophyton benhamiae [88]. While this most recent study confirmed the critical role of Th17 cells in protection from dermatophytosis, it reported a synergistic instead of an antagonistic role of IL-17- and IFN-γ-producing T cells to facilitate optimal fungal clearance [88]. The discrepancy between the two studies may be explained by differences in the two fungal genera, the mouse background and microbial status and/or details in the experimental protocol including the preparation of the mice for infection.…”

“…Analyzing the host response to dermatophytes in IL-17-deficient animals revealed that IL-17 not only limits dermatophyte growth on the skin, but also antagonizes a non-protective Th1 response against the fungus, which in the absence of IL-17 resulted in excessive skin inflammation and fungal overgrowth [87]. A similar protective role for Th17 has been demonstrated against the dermatophyte Trichophyton benhamiae [88]. While this most recent study confirmed the critical role of Th17 cells in protection from dermatophytosis, it reported a synergistic instead of an antagonistic role of IL-17- and IFN-γ-producing T cells to facilitate optimal fungal clearance [88].…”

In situ immune response in human dermatophytosis: possible role of Langerhans cells (CD1a+) as a risk factor for dermatophyte infection

“…Regarding the first possibility, it has been described that T. rubrum releases a variety of molecules, including proteases 30-32 , that can interact with host cells and eventually lead to down regulation of the expression of surface markers such as CD1a in LCs, thereby interfering with their function. In our second hypothesis, activated skin APCs migrate to regional lymph nodes to induce adaptive immune responses, but the systemic cellular immune response of dermatophytosis patients shows a tendency towards a non-protective, pathology-inducing, Th-2 13,33,34 response, even though their LCs are able to produce pro-inflammatory mediators, IL-12 included, locally 35 . Thus, we hypothesize that T. rubrum (or its products)-mediated activation and migration of LCs from the epidermis would not necessarily result in better in situ protective responses.…”

“…Recently, several reports described severe and occasionally life-threatening invasive disease (deep dermatophytosis) associated to genetic mutations in the innate immunity-associated molecule CARD9 6,8,11 , highlighting the need to better understand the immune response in this infection. Recently, studies in animal models of dermatophytosis have demonstrated that Th17 and eventually Th1 immune responses were essential to the optimal control of this fungal infection 12,13 .…”

Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease

“…In contrast, Baltazar et al (112) reported that IL-12p40 KO mice (lacking common b-subunit of IL-12 and IL-23 and thus, with impaired IL-17 and IFN-g signaling) or IFN-g KO mice were able to control T. rubrum infection after 14 days, but showed an increased fungal burden in the first week compared to infected WT mice. Eventually, as described for the M. canis model (51), deep dermatophytosis was not observed in the absence of IL-17 and IFN-g in neither infection models (112,120), suggesting that several immune pathways must be compromised to establish invasive dermatophytosis. The effector mechanisms of IFN-g remains unclear but Verma and Gaffen (121) hypothesized that, as observed in Candida skin infection, IFN-g may contribute to T. benhamiae destruction and expulsion by activating the fibrinolytic system in the epidermal abscess (122) or promoting M1 macrophages at a later infection stage ( Figure 2).…”