Regulatory T cells control Th1 responses to sustain bacterial immunity and skin barrier function

Abstract

Abstract Commensals actively contribute to homeostasis in the skin, but a perturbation of the skin bacteria leading to a dysbiosis often promotes increased inflammation. How regulatory mechanisms control the degree of inflammation associated with a dysbiosis is unclear. Here we used a Staphylococcus aureus isolate from Leishmania braziliensis patients to study the regulation of the host immune response in the skin and its consequence during cutaneous leishmaniasis. Topical colonization with S. aureus induced type 17 responses with minimal skin inflammation. Analysis of Foxp3+ Treg cells revealed IL-6 dependent accumulation of Blimp-1 expressing RORgt+Foxp3+ Treg cells in colonized skin, and that may play a protective regulatory role. To test this, we depleted Foxp3+ Treg cells, which resulted in significant inflammation and a higher bacterial burden on the skin. Additionally, there was some decrease in IL-17 responses, but a significant increase in the IFN-γ production from CD4+ T cells. Moreover, blockade of IFN-γ in Foxp3+ Treg depleted mice restored commensal immunity, barrier function and inflammation. In mice infected with L. braziliensis, depletion of Foxp3+ T cells had a minimal effect on lesion development. However, depletion of Foxp3+ T cells in S. aureus colonized and L. braziliensis infected mice resulted in significantly more inflammation and bacterial burden than control mice without altering the parasite burden. Taken together, we identified a role for Foxp3+ Treg cells in limiting inflammatory responses to skin bacteria by controlling production of IFN-γ by CD4+ T cells.