CD8+ Granzyme B+–Mediated Tissue Injury vs. CD4+IFNγ+–Mediated Parasite Killing in Human Cutaneous Leishmaniasis

摘要

A protective or deleterious role of CD8⁺T cells in human cutaneous leishmaniasis (CL) has been debated. The present report explores the participation of CD8⁺T cells in disease pathogenesis as well as in parasite killing. CD8⁺T cells accumulated in CL lesions as suggested by a higher frequency of CD8⁺CD45RO⁺T cells and CD8⁺CLA⁺T cells compared with peripheral blood mononuclear cells. Upon Leishmania braziliensis restimulation, most of the CD8⁺T cells from the lesion expressed cytolytic markers, CD107a and granzyme B. Granzyme B expression in CL lesions positively correlated with lesion size and percentage of TUNEL-positive cells. We also observed a significantly higher percentage of TUNEL-positive cells and granzyme B expression in the biopsies of patients showing a more intense necrotic process. Furthermore, coculture of infected macrophages and CD8⁺T lymphocytes resulted in the release of granzyme B, and the use of granzyme B inhibitor, as well as z-VAD, Fas:Fc, or anti-IFN-γ, had no effect upon parasite killing. However, coculture of infected macrophages with CD4⁺T cells strongly increased parasite killing, which was completely reversed by anti-IFN-γ. Our results reveal a dichotomy in human CL: CD8⁺ granzyme B⁺T cells mediate tissue injury, whereas CD4⁺IFN-γ⁺T cells mediate parasite killing.