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

Trautwein-Weidner K, Gladiator A, Kirchner FR, Becattini S, Rülicke T, Sallusto F, LeibundGut-Landmann S - PLoS Pathog. (2015)

Bottom Line: The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus

Flt3L-dependent migratory DCs and monocyte-derived DCs complement each other for Th17 priming during OPC.(A) Cervical lymph nodes were isolated from B6 and Flt3l-/- mice on day 7 post-infection and re-stimulated with heat-killed (h.k.) C. albicans or medium only. IL-17A production by endogenous CD3+ CD4+ cells was then analyzed by flow cytometry. (B) B6 and Ccr2-/- mice were infected sublingually and IL-17 production by endogenous CD3+ CD4+ cells was analyzed on day 7 post-infection as described in (A). (C) B6 mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). (D) B6 and Flt3l-/- mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). Each symbol represents one mouse, the mean + SD for each group is shown.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4591991&req=5

ppat.1005164.g007: Flt3L-dependent migratory DCs and monocyte-derived DCs complement each other for Th17 priming during OPC.(A) Cervical lymph nodes were isolated from B6 and Flt3l-/- mice on day 7 post-infection and re-stimulated with heat-killed (h.k.) C. albicans or medium only. IL-17A production by endogenous CD3+ CD4+ cells was then analyzed by flow cytometry. (B) B6 and Ccr2-/- mice were infected sublingually and IL-17 production by endogenous CD3+ CD4+ cells was analyzed on day 7 post-infection as described in (A). (C) B6 mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). (D) B6 and Flt3l-/- mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). Each symbol represents one mouse, the mean + SD for each group is shown.

Mentions: To evaluate the relative contribution of CCR2-dependent and Flt3L-dependent migratory DC subsets in T cell priming during OPC in vivo, we examined the induction of C. albicans-specific Th17 cell in the cervical lymph nodes of OPC infected Flt3l-/- and Ccr2-/- mice on day 7 post-infection. While the response was not affected by the absence of Flt3L-dependent DCs (Fig 7A), the frequency of IL-17-secreting C. albicans-specific CD4+ T was strongly reduced in Ccr2-/- mice compared to B6 controls (Fig 7B). Similarly to the endogenous response, adoptively transferred Hector T cells were also strongly impaired in their capacity to differentiate into IL-17-producing effector cells in Ccr2-/- mice (S6 Fig). Alterations in DC and monocyte populations may impair the innate control of the fungus; and an increased fungal burden can augment the extent of the T cell response. Therefore, to exclude the possibility that the results were influenced by differences in the available amount of antigen between the experimental groups, we treated the mice with Fluconazole from day 2 post-infection, a time point when the fungal burden was high and similar in all groups of mice (S7 Fig). This resulted in comparable weight recovery (S7 Fig) and clearance of the fungus to undetectable levels within the period of the experiment, which is indicative of comparable infection control in all experimental groups.


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

Trautwein-Weidner K, Gladiator A, Kirchner FR, Becattini S, Rülicke T, Sallusto F, LeibundGut-Landmann S - PLoS Pathog. (2015)

Flt3L-dependent migratory DCs and monocyte-derived DCs complement each other for Th17 priming during OPC.(A) Cervical lymph nodes were isolated from B6 and Flt3l-/- mice on day 7 post-infection and re-stimulated with heat-killed (h.k.) C. albicans or medium only. IL-17A production by endogenous CD3+ CD4+ cells was then analyzed by flow cytometry. (B) B6 and Ccr2-/- mice were infected sublingually and IL-17 production by endogenous CD3+ CD4+ cells was analyzed on day 7 post-infection as described in (A). (C) B6 mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). (D) B6 and Flt3l-/- mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). Each symbol represents one mouse, the mean + SD for each group is shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591991&req=5

ppat.1005164.g007: Flt3L-dependent migratory DCs and monocyte-derived DCs complement each other for Th17 priming during OPC.(A) Cervical lymph nodes were isolated from B6 and Flt3l-/- mice on day 7 post-infection and re-stimulated with heat-killed (h.k.) C. albicans or medium only. IL-17A production by endogenous CD3+ CD4+ cells was then analyzed by flow cytometry. (B) B6 and Ccr2-/- mice were infected sublingually and IL-17 production by endogenous CD3+ CD4+ cells was analyzed on day 7 post-infection as described in (A). (C) B6 mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). (D) B6 and Flt3l-/- mice were treated with anti-CSF1R or left untreated prior to sublingual infection with C. albicans. IL-17 production by endogenous CD3+ CD4+ cervical lymph node cells was analyzed on day 7 post-infection as described in (A). Each symbol represents one mouse, the mean + SD for each group is shown.
Mentions: To evaluate the relative contribution of CCR2-dependent and Flt3L-dependent migratory DC subsets in T cell priming during OPC in vivo, we examined the induction of C. albicans-specific Th17 cell in the cervical lymph nodes of OPC infected Flt3l-/- and Ccr2-/- mice on day 7 post-infection. While the response was not affected by the absence of Flt3L-dependent DCs (Fig 7A), the frequency of IL-17-secreting C. albicans-specific CD4+ T was strongly reduced in Ccr2-/- mice compared to B6 controls (Fig 7B). Similarly to the endogenous response, adoptively transferred Hector T cells were also strongly impaired in their capacity to differentiate into IL-17-producing effector cells in Ccr2-/- mice (S6 Fig). Alterations in DC and monocyte populations may impair the innate control of the fungus; and an increased fungal burden can augment the extent of the T cell response. Therefore, to exclude the possibility that the results were influenced by differences in the available amount of antigen between the experimental groups, we treated the mice with Fluconazole from day 2 post-infection, a time point when the fungal burden was high and similar in all groups of mice (S7 Fig). This resulted in comparable weight recovery (S7 Fig) and clearance of the fungus to undetectable levels within the period of the experiment, which is indicative of comparable infection control in all experimental groups.

Bottom Line: The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbiology, ETH Zürich, Zürich, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus