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.

Keywords: anti-TNF; dendritic cell; dendritic cells; fungus; imaging flow cytometry; intracellular fungi; lung; lung infection; rodent; tumor necrosis factor.