Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis

Abstract

Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood. Here we generated a Candida-specific TCR transgenic mouse reactive to a novel endogenous antigen that is conserved in multiple distant species of Candida, including the clinically highly relevant C. albicans and C. glabrata. Using TCR transgenic T cells in combination with an experimental model of oropharyngeal candidiasis (OPC) we investigated antigen presentation and Th17 priming by different subsets of dendritic cells (DCs) present in the infected oral mucosa. Candida-derived endogenous antigen accesses the draining lymph nodes and is directly presented by migratory DCs. Tissue-resident Flt3L-dependent DCs and CCR2-dependent monocyte-derived DCs collaborate in antigen presentation and T cell priming during OPC. In contrast, Langerhans cells, which are also present in the oral mucosa and have been shown to prime Th17 cells in the skin, are not required for induction of the Candida-specific T cell response upon oral challenge. This highlights the functional compartmentalization of specific DC subsets in different tissues. These data provide important new insights to our understanding of tissue-specific antifungal immunity.

Author Summary

Candida spp. are present in the normal microbiota without causing damage to the host. They can become pathogenic and bear a serious health hazard for individuals with a weakened immune system. The continuous incidence of fungal infections and the increase in resistance against available antifungal drugs urge the development of novel preventive and therapeutic strategies. Knowledge gained from understanding how immunocompetent mammals control Candida will help develop new immunotherapeutic and-prophylactic approaches suitable to improve patient prognosis. It is well known that T helper cells, and in particular the Th17 subset, provide resistance against mucocutaneous infections with Candida. However, the mechanisms through which T cell-mediated antifungal immunity is induced in such context are not well understood. Here we developed a new experimental system to study the regulation of antigen-specific T cells with high resolution. Our results reveal the interplay of different dendritic cell subsets associated to the oral mucosa of infected mice that directly present fungal antigen to Candida-specific T cells and orchestrate a protective Th17 response in a tissue specific manner. Thus, our data highlight important features of immune regulation in the oral mucosa, a tissue that is immunologically not well characterized.