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-gamma, 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.
Anderson
Charles F
CF
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Oukka
Mohammed
M
Kuchroo
Vijay J
VJ
Sacks
David
D
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D015151:Immunoblotting; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D016753:Interleukin-10; D007371:Interferon-gamma