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

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 in-fected with Histoplasma capsulatum. Lung CD11c(+) CD11 b(+) dendritic cells (DCs), but not alveolar macrophages, from H. capsulatum-mfected mice treated with anti-TNF induced a higher percentage of Tregs than control DCs in vitro. CD11 b(+) 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. CD11 b(+ )CD103 (+) DCs from TNF-neutralized mice displayed higher retinaldehyde dehydrogenase 2 (RALDH2) gene expression, and CD11 b(+) CD103 (+) RALDH (+) DCs exhibited greater enzyme activity. To determine if CD11 b(+) 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 in-duced migration of CD11 b(+) CD103 (+) DCs from the gut to the lung that enhanced the generation of Tregs in H. capsulatum-mfected mice. Therefore, TNF neutralization promotes susceptibility to pulmonary H. capsulatum infection by promoting a gut/ lung migration of DCs that enhances Tregs.