CD4⁺CD25⁻Foxp3⁻ Th1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis

Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell–polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25⁻Foxp3⁻ T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4⁺CD25⁻Foxp3⁻ T cells, the majority of which also produced IFN-γ, was necessary for suppression of acquired immunity in Rag^−/− reconstituted mice. Surprisingly, Rag^−/− mice reconstituted with naive CD4⁺ T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10–producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell–derived IL-10–dependent immune suppression in a chronic intracellular infection.