Cutaneous leishmaniasis causes alterations in the skin microbiota, leading to pathologic immune responses and delayed healing. However, it is not known how these microbiota-driven immune responses are regulated. Here, we report that depletion of Foxp3+ regulatory T cells (Tregs) in Staphylococcus aureus–colonized mice resulted in less IL-17 and an IFN-γ–dependent skin inflammation with impaired S. aureus immunity. Similarly, reducing Tregs in S. aureus–colonized and Leishmania braziliensis–infected mice increased IFN-γ, S. aureus, and disease severity. Importantly, analysis of lesions from L. braziliensis patients revealed that low FOXP3 gene expression is associated with high IFNG expression, S. aureus burden, and delayed lesion resolution compared to patients with high FOXP3 expression. Thus, we found a critical role for Tregs in regulating the balance between IL-17 and IFN-γ in the skin, which influences both bacterial burden and disease. These results have clinical ramifications for cutaneous leishmaniasis and other skin diseases associated with a dysregulated microbiome when Tregs are limited or dysfunctional.

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