R MARZI¹, G GYUELVESZI¹, S BECATTINI¹, B BECHER², S LEIBUNDGUT-LANDMANN³, F SALLUSTO<sup>1

1</sup>Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland, ²Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland, ³Section of Immunology, Institute of Virology, University of Zurich, Zurich, Switzerland

Vulvovaginal candidiasis (VVC) is the most common manifestation of C. albicans infection, affecting ~75% of healthy women worldwide during their childbearing age. Chronic mucocutaneous candidiasis (CMC) patients with mutations in genes associated with the IL-17 pathway display symptoms of VVC (in addition to oral candidiasis), but whether the disruption of the IL-17 pathway is a direct cause for VVC or rather an indirect effect due to the general increase in fungal colonization in these patients is unclear. Mice lacking IL-23, either IL-17R subunit or the adaptor Act1, are susceptible to oral and dermal candidiasis. However, IL-17RA–/– and IL-23–/– mice are not susceptible to vaginal infection. These previous studies analyzed only the early phases of the host-pathogens interplay, which is generally life-long in humans. In this study, we set out kinetic experiments to assess the relative contribution of Th17 cells in persistent VVC. We found that wild type (WT) mice, CD3ε–/– mice, lacking T cells, and μMT mice, lacking B cells, rapidly recovered from infection. However, while WT and μMT mice survived even at later time points (>90 days), completely recovering from the infection, CD3ε–/– mice succumbed to the challenge. CFU assessment from collected organs revealed massive C. albicans presence in vagina, ovary/uterus, gut and stomach in CD3e–/– mice, implicating failure of containment strategies. In order to define the mechanism of T cell-mediated protections, we adoptively transferred CD3ε–/– mice with WT, IL-22–/– or IL-17–/– CD4+ T cells before vaginal infection. CD3ε–/– mice transferred with WT or IL-22–/– CD4+ T cells, that produce normal amount of IL-17, survived upon challenge, while mice transferred with IL-17–/– CD4+ T cells succumbed at late time points as CD3ε–/– mice. We are currently performing experiments of adoptive transfer with Candida-specific TCR-transgenic T cells to follow T cell differentiation and assess T cell plasticity. Our results suggest that, although not required in the initial phase of the challenge, IL-17 production by Th cells is required for long-term containment of C. albicans vaginal infection.