Fungi Subvert Vaccine T Cell Priming at the Respiratory Mucosa by Preventing Chemokine-Induced Influx of Inflammatory Monocytes

Wüthrich, Marcel; Ersland, Karen; Sullivan, Thomas D.; Galles, Kevin; Klein, Bruce S.

doi:10.1016/j.immuni.2012.02.015

Cited by 61 publications

(76 citation statements)

References 32 publications

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“…In the lung, Ly6C hi monocytes and derivative Mo-DCs transport A. fumigatus conidia and B. dermatiditis yeast cells to lung-draining lymph nodes (121,122). In a B. dermatiditis vaccine model, fungal protease-dependent cleavage of CCR2 ligands impedes lung Ly6C hi monocyte trafficking and the development of vaccine protection (123). However, Mo-DCs are not required for direct CD4 + T cell priming due to antigen transfer to lymph node-resident DCs (122).…”

Section: Il-17mentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

117

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Section: Il-17mentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

117

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“…They are rapidly recruited at the infection locations. [102][103][104][105] Monocytes mainly recognize invading fungi in circulation, expressing high levels of TLRs and moderate levels of CLRs. 21 When monocytes reside at infected tissues and differentiate into macrophages, they keep on expressing TLRs and upregulate the expression of CLRs.…”

Section: Prrs Of Neutrophils and Monocytes/macrophagesmentioning

confidence: 99%

The role of pattern recognition receptors in the innate recognition ofCandida albicans

Zheng

Wang

et al. 2015

Virulence

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“…However, the downstream effector, memory, and recall functions of TEa cells were blunted by insufficient Ag display on the vaccine yeast. Thus, this TEa Tg system is ideally suited to studying fungal Ag presentation and early T cell priming, whereas T cell effector and memory development may instead be studied with the autologous TCR Tg 1807 cells described recently (37).…”

Section: Discussionmentioning

confidence: 99%

“…To identify the transgenepositive progeny, lymphocytes from peripheral blood were stained with phycoerythrin (PE)-Cy7-labeled anti-CD4, fluorescein isothiocyanate (FITC)-labeled anti-V␣2, and PE-labeled anti-V␤6 antibodies (BD Pharmingen) and analyzed by fluorescence-activated cell sorter (FACS) analysis as previously described (15). Blastomyces-specific TCR Tg strain 1807 mice were generated in the Klein lab and described elsewhere (37,42,43). Strain 1807 mice were backcrossed to congenic Thy1.1-positive (Thy1.1 ϩ ) mice as described above.…”

Section: Methodsmentioning

confidence: 99%

“…The preceding studies with Tg yeasts expressing E␣ and 2W1S suggest that low antigen expression may have limited the development of effector T cells. To investigate whether endogenous fungal antigens prime naïve CD4 ϩ T cells more efficiently than the model antigens, we adoptively transferred naïve B. dermatitidis-specific 1807 cells into mice prior to vaccination with BAD1-null yeasts that do not express model antigens (6,37). Comparable numbers of polyclonal CD4 ϩ T cells migrated into the lungs after challenge and expressed gamma interferon (IFN-␥) in mice that had received adoptively transferred TEa or 1807 cells and were vaccinated with E␣-mCh yeast or BAD1-null yeast (Fig.…”

Section: Impact Of Precursor Frequency and Vaccine Dose On T Cell Expmentioning

confidence: 99%

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Limited Model Antigen Expression by Transgenic Fungi Induces Disparate Fates during Differentiation of Adoptively Transferred T Cell Receptor Transgenic CD4 ⁺ T Cells: Robust Activation and Proliferation with Weak Effector Function during Recall

et al. 2012

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Diseases due to fungi represent a growing public health problem that demand new treatments and methods of vaccine prevention (8). The rational design of vaccines against fungi requires an understanding of the elements of antifungal immunity. Cellular immunity is pivotal in acquired resistance to fungal infections and is organized into clonal populations of antigen (Ag)-specific CD4 ϩ T cells (8,30,40). The ability to track, enumerate, and characterize Ag-specific T cells precisely requires knowledge of the Ag peptide. With such information, peptide-major histocompatibility complex (MHC) tetramers and T cell receptor (TCR) transgenic (Tg) mice have been used to track and enumerate Ag-specific T cells ex vivo to circumvent in vitro expansion or distortion of immune responses.Reagents are available to precisely study T cell immunity with model agents such as lymphocytic choriomeningitis virus and Listeria (9, 22), but the study of most other pathogens is not readily approachable with these high-resolution methods. For the systemic dimorphic fungi, no T cell Ag epitopes have been elucidated to provide the tools to address this gap in knowledge. To bridge this gap, we engineered heterologous Ag and epitopes into a vaccine strain of a pathogenic fungus to let us induce, track, quantify, characterize, and functionally analyze adoptively transferred TCR Tg T cells specific for the foreign Ag in vaccinated animals.Blastomycosis is a systemic infection due to the dimorphic fungus Blastomyces dermatitidis. We have created a live attenuated vaccine against lethal experimental infection (38). The vaccine induces sterilizing immunity that is mediated by CD4 ϩ T cells, although the protective antigen remains unknown. Still, this model and the potent activity of these CD4 ϩ T cells offer the chance to elucidate the requirements for inducing and maintaining antifungal CD4 ϩ T cells by vaccination. As a surrogate means to study the in vivo activation, proliferation, and maintenance of Blastomyces-specific CD4 ϩ T cells, we expressed model epitopes on the vaccine B. dermatitidis yeast using BAD1, an abundant surface protein, as a carrier. Yeast surface Ag display is thought to be one feature that promotes the generation of antifungal immune responses.In other nonfungal models, the availability of Ag and the number of naïve T cell precursors in a host can affect the priming and development of CD4 ϩ effector and memory T cells (1, 27). However, little is known about the identity, cellular distribution, and expression levels of fungal T cell epitopes and how these factors influence the development of antifungal immunity. We report that expressing a model epitope such as E␣ peptide on vaccine yeast induced the activation and proliferation of corresponding naïve, adoptively transferred TCR Tg TEa cells. We describe the experimental system and our results enabling the tracking of fungal Ag presentation to CD4 ϩ T cells and the corresponding Agspecific T cell response during their earliest stages of activation, proliferation, and expansi...

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Fungi Subvert Vaccine T Cell Priming at the Respiratory Mucosa by Preventing Chemokine-Induced Influx of Inflammatory Monocytes

Cited by 61 publications

References 32 publications

Immunity against fungi

Immunity against fungi

The role of pattern recognition receptors in the innate recognition ofCandida albicans

Limited Model Antigen Expression by Transgenic Fungi Induces Disparate Fates during Differentiation of Adoptively Transferred T Cell Receptor Transgenic CD4 ⁺ T Cells: Robust Activation and Proliferation with Weak Effector Function during Recall

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Fungi Subvert Vaccine T Cell Priming at the Respiratory Mucosa by Preventing Chemokine-Induced Influx of Inflammatory Monocytes

Cited by 61 publications

References 32 publications

Immunity against fungi

Immunity against fungi

The role of pattern recognition receptors in the innate recognition ofCandida albicans

Limited Model Antigen Expression by Transgenic Fungi Induces Disparate Fates during Differentiation of Adoptively Transferred T Cell Receptor Transgenic CD4 + T Cells: Robust Activation and Proliferation with Weak Effector Function during Recall

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Limited Model Antigen Expression by Transgenic Fungi Induces Disparate Fates during Differentiation of Adoptively Transferred T Cell Receptor Transgenic CD4 ⁺ T Cells: Robust Activation and Proliferation with Weak Effector Function during Recall