Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation.

Pulmonary infection of mice with Aspergillus fumigatus induces concurrent T helper type 1 (Th1) and Th17 responses that depend on Toll-like receptor/MyD88 and Dectin-1, respectively. However, the mechanisms balancing Th1 and Th17 CD4 T cell populations during infection remain incompletely defined. In this study, we show that Dectin-1 deficiency disproportionally increases Th1 responses and decreases Th17 differentiation after A. fumigatus infection. Dectin-1 signaling in A. fumigatus-infected wild-type mice reduces IFN-γ and IL-12p40 expression in the lung, thereby decreasing T-bet expression in responding CD4 T cells and enhancing Th17 responses. Absence of IFN-γ or IL-12p35 in infected mice or T-bet in responding CD4 T cells enhances Th17 differentiation, independent of Dectin-1 expression, in A. fumigatus-infected mice. Transient deletion of monocyte-derived dendritic cells also reduces Th1 and boosts Th17 differentiation of A. fumigatus-specific CD4 T cells. Our findings indicate that Dectin-1-mediated signals alter CD4 T cell responses to fungal infection by decreasing the production of IL-12 and IFN-γ in innate cells, thereby decreasing T-bet expression in A. fumigatus-specific CD4 T cells and enabling Th17 differentiation.

Aberrant tissue localization of fungus-specific CD4+ T cells in IL-10-deficient mice.

Aspergillus fumigatus, a common environmental fungus, can cause lethal invasive infections in immunocompromised hosts. In immunocompetent individuals, however, inhaled A. fumigatus spores prime CD4(+) T cells and activate immune responses that prevent invasive infection. Calibration of inflammatory responses to levels that prevent fungal invasion without inducing collateral tissue damage is essential for host survival, but the underlying regulatory mechanisms remain undefined. Although IL-10 is a validated regulatory cytokine that suppresses immune responses, and IL-10 deficiency or blockade generally enhances immune responses, we find that A. fumigatus-specific T cell frequencies are markedly reduced in airways of IL-10-deficient mice. T cell priming, proliferation, and survival were unaffected by IL-10 deficiency and did not account for decreased frequencies of A. fumigatus-specific T cells in the airways of IL-10-deficient mice. Instead, IL-10 deficiency results in redistribution of A. fumigatus-specific T cells from infected lungs to the gut, a process that is reversed by antibiotic-mediated depletion of intestinal microbes. Our studies demonstrate that disregulated immune responses in the gut can result in dramatic redistribution of pathogen-specific T cells within the host.