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

André Gladiator,Mairi C Noverr,Kerstin Trautwein-Weidner,Federica Sallusto,Salomé Leibundgut-Landmann,Simone Becattini,Florian R Kirchner,Thomas Rülicke

doi:10.1371/journal.ppat.1005164

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.

Highlights

Opportunistic fungal infections cause an increasing medical problem due to the progression in immunosuppression worldwide [1]
Candida-specific memory T helper cells are found in all healthy individuals that have been exposed to the fungus in the normal human microflora and interestingly, they belong predominantly to the subset of Interleukin 17 (IL-17)-secreting Th17 cells [3]
In this mouse, dubbed 'Hector', 40–60% of all peripheral CD4+ T cells expressed a transgenic T cell receptors (TCRs) consisting of Vα2 and Vβ4 genes sequenced from the T cell hybridoma 59.8, which was generated from T cells that were isolated from a C. albicansinfected C57BL/6J (B6) mouse (S1 Fig)

Summary

Introduction

Opportunistic fungal infections cause an increasing medical problem due to the progression in immunosuppression worldwide [1]. Only few TCR transgenic mouse lines specific for clinically relevant pathogens including fungi [5,6] exist to date To circumvent this limitation, well-established TCR transgenic T cells specific for model antigens such as ovalbumin or the I-Eα chain have been used in combination with infectious agents engineered to express these model antigens. Well-established TCR transgenic T cells specific for model antigens such as ovalbumin or the I-Eα chain have been used in combination with infectious agents engineered to express these model antigens Such systems are useful to interrogate the activation of antigen-specific T cells in the context of an infectious setting, they have important limitations, such as restricted availability, processing and presentation of model antigens during T cell priming that result in the inefficient generation of effector and memory T cells [7]. No TCR transgenic mouse specific for Candida spp. exists to date

Methods

Results

Discussion

Conclusion