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Tumor Necrosis Factor Alpha Antagonism Reveals a Gut/Lung Axis That Amplifies Regulatory T Cells in a Pulmonary Fungal Infection.

ABSTRACT: Tumor necrosis factor (TNF) antagonists are popular therapies for inflammatory diseases. These agents enhance the numbers and function of regulatory T cells (Tregs), which are important in controlling inflammatory diseases. However, elevated Treg levels increase susceptibility to infections, including histoplasmosis. We determined the mechanism by which Tregs expand in TNF-neutralized mice infected with Histoplasma capsulatum Lung CD11c+ CD11b+ dendritic cells (DCs), but not alveolar macrophages, from H. capsulatum-infected mice treated with anti-TNF induced a higher percentage of Tregs than control DCs in vitro CD11b+ CD103+ DCs, understood to be unique to the intestines, were augmented in lungs with anti-TNF treatment. In the absence of this subset, DCs from anti-TNF-treated mice failed to amplify Tregs in vitro CD11b+ CD103+ DCs from TNF-neutralized mice displayed higher retinaldehyde dehydrogenase 2 (RALDH2) gene expression, and CD11b+ CD103+ RALDH+ DCs exhibited greater enzyme activity. To determine if CD11b+ CD103+ DCs migrated from gut to lung, fluorescent beads were delivered to the gut via oral gavage, and the lungs were assessed for bead-containing DCs. Anti-TNF induced migration of CD11b+ CD103+ DCs from the gut to the lung that enhanced the generation of Tregs in H. capsulatum-infected mice. Therefore, TNF neutralization promotes susceptibility to pulmonary H. capsulatum infection by promoting a gut/lung migration of DCs that enhances Tregs.

SUBMITTER: Tweedle JL

PROVIDER: S-EPMC5964519 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Tumor Necrosis Factor Alpha Antagonism Reveals a Gut/Lung Axis That Amplifies Regulatory T Cells in a Pulmonary Fungal Infection.

Tweedle Jamie L JL Deepe George S GS

Infection and immunity 20180522 6

Tumor necrosis factor (TNF) antagonists are popular therapies for inflammatory diseases. These agents enhance the numbers and function of regulatory T cells (Tregs), which are important in controlling inflammatory diseases. However, elevated Treg levels increase susceptibility to infections, including histoplasmosis. We determined the mechanism by which Tregs expand in TNF-neutralized mice infected with Histoplasma capsulatum Lung CD11c+ CD11b+ dendritic cells (DCs), ...[more]

PMID: 29581197

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Dataset Information

Tumor Necrosis Factor Alpha Antagonism Reveals a Gut/Lung Axis That Amplifies Regulatory T Cells in a Pulmonary Fungal Infection.

Publications

Tumor Necrosis Factor Alpha Antagonism Reveals a Gut/Lung Axis That Amplifies Regulatory T Cells in a Pulmonary Fungal Infection.

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