CD8+ T Cells Lack Local Signals To Produce IFN-γ in the Skin during Leishmania Infection

Abstract

Resolution of leishmaniasis depends upon parasite control and limiting inflammation. CD4⁺ Th1 cells are required to control parasites, whereas CD8⁺ T cells play a dual role: they promote Th1 cell differentiation but can also increase inflammation at the site of infection as a consequence of cytolysis. Although CD8⁺ T cells taken from leishmanial lesions are cytolytic, in this study, we showed that only a few CD8⁺ T cells produced IFN-γ. Correspondingly, only low levels of IL-12 and/or IL-12 mRNA were present in lesions from infected mice, as well as patients. Addition of IL-12 increased IFN-γ production by CD8⁺ T cells isolated from leishmanial lesions, suggesting that a lack of IL-12 at the site of infection limits IFN-γ production by CD8⁺ T cells. To determine whether CD8⁺ T cells could promote resistance in vivo if IL-12 was present, we administered IL-12 to Leishmania-infected RAG mice reconstituted with CD8⁺ T cells. IL-12 treatment increased the ability of CD8⁺ T cells to make IFN-γ, but CD8⁺ T cells still failed to control the parasites. Furthermore, despite the ability of CD8⁺ T cells to promote immunity to secondary infections, we also found that CD8⁺ T cells from immune mice were unable to control Leishmania in RAG mice. Taken together, these results indicate that lesional CD8⁺ T cells fail to make IFN-γ because of a deficit in IL-12 but that, even with IL-12, CD8⁺ T cells are unable to control Leishmania in the absence of CD4⁺ T cells.