Early innate events that enable priming of antifungal CD4 T cells are poorly understood. We engineered an attenuated fungal vaccine with a model epitope, EalphaRFP, to track vaccine immunity to Blastomyces dermatitidis during yeast recognition, antigen presentation, and priming of naive T cells. After subcutaneous injection of the vaccine, monocyte-derived inflammatory dendritic cells (DCs) are the earliest and largest population that associates with yeast, carrying them into the draining lymph nodes. Despite marked association with yeast, these DCs fail to display surface peptide:MHC complexes or prime naive T cells. Instead, the ability to display antigen and prime CD4 T cells resides with lymph node-resident DCs after antigen transfer from immigrant DCs and with skin migratory DCs. Our work reveals the dynamic interplay among distinct DC subsets that prime naive CD4 T cells after yeast are injected in the skin and discloses the cellular elements underlying vaccine-induced immunity to fungi.
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"Depletion of CCR2 + moDCs at later stages of infection, leads to a skewing from a Th1 to a Th17 response in the lung, which indicates that recruitment of monocytes has an influential role in shaping the adaptive immune response and are necessary to promote and sustain Th1 responses (Rivera et al., 2011). Studies with other fungal pathogens further support a conserved function for moDCs in shaping fungus-specific CD4 + T cell responses (Traynor et al., 2002; Szymczak and Deepe, 2009; Ersland et al., 2010; Szymczak and Deepe, 2010; Wüthrich et al., 2012b). In addition to their importance in shaping fungus-specific CD4 + T cell responses, CCR2 + Mo and moDCs are important direct effectors necessary for prevention of IA (Espinosa et al., 2014). "
[Show abstract][Hide abstract]ABSTRACT: Mycotic infections and their effect on the human condition have been widely overlooked and poorly surveilled by many health organizations even though mortality rates have increased in recent years. The increased usage of immunosuppressive and myeloablative therapies for the treatment of malignant as well as non-malignant diseases has contributed significantly to the increased incidence of fungal infections. Invasive fungal infections have been found to be responsible for at least 1.5 million deaths worldwide. About 90% of these deaths can be attributed to Cryptococcus, Candida, Aspergillus, and Pneumocystis. A better understanding of how the host immune system contains fungal infection is likely to facilitate the development of much needed novel antifungal therapies. Innate cells are responsible for the rapid recognition and containment of fungal infections and have been found to play essential roles in defense against multiple fungal pathogens. In this review we summarize our current understanding of host-fungi interactions with a focus on mechanisms of innate cell-mediated recognition and control of pulmonary aspergillosis.
Full-text · Article · Mar 2016 · Frontiers in Microbiology
"During pulmonary aspergillosis, blastomycosis vaccine challenge, and oropharyngeal candidiasis, Ly6C hi monocyte-derived Mo-DCs play an essential role in transporting fungal antigens from the lung or oral cavity to draining lymph nodes [32,113,114] (Fig. 1C ). However , Mo-DCs do not appear essential for CD4 T cell priming beyond their role in antigen transport to draining LNs, since fungal antigen is transferred among a subset of LN-resident DCs that prime antigen-specific CD4 T cells in vivo [113,114]. Consistent with this model, MHC class II expression on Ly6C hi monocytes and their derivative cells is dispensable for the development of antigenspecific CD4 T cells against M. tuberculosis in the lung . "
[Show abstract][Hide abstract]ABSTRACT: Circulating blood monocytes are a heterogeneous leukocyte population that contributes critical antimicrobial and regulatory functions during systemic and tissue-specific infections. These include patrolling vascular tissue for evidence of microbial invasion, infiltrating peripheral tissues and directly killing microbial invaders, conditioning the inflammatory milieu at sites of microbial tissue invasion, and orchestrating the activation of innate and adaptive immune effector cells. The central focus of this review is the in vivo mechanisms by which monocytes and their derivative cells promote microbial clearance and immune regulation. We include an overview of murine models to examine monocyte functions during microbial challenges and review our understanding of the functional roles of monocytes and their derivative cells in host defense against bacteria, fungi, and parasites.
Full-text · Article · Mar 2016 · Seminars in Immunology
"Interrupting the differentiation of monocyte into DCs in absence of Flt3-dependent DCs almost abolished T cell priming, supporting the notion that other Flt3-independent DCs such as Langerhans cells are not required and not sufficient for Th17 induction during OPC. Monocyte-derived DCs gain increasing attention for their role as professional APC to promote T cell responses525354 including those elicited by fungi such as Aspergillus fumigatus or Blastomyces dermatitidis [55,56]. In addition to priming adaptive immunity, CCR2-dependent cells also contribute to innate immunity against fungi including C. albicans and A. fumigatus Antigen-Specific Th17 Priming during Oropharyngeal Candidiasis [57,58]. "
[Show abstract][Hide abstract]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.