CD8þ Granzyme Bþ–Mediated Tissue Injury vs. CD4þIFNcþ–Mediated Parasite Killing in Human Cutaneous Leishmaniasis

Abstract

A protective or deleterious role of CD8þT cells in human cutaneous leishmaniasis (CL) has been debated. The present report explores the participation of CD8þT cells in disease pathogenesis as well as in parasite killing. CD8þT cells accumulated in CL lesions as suggested by a higher frequency of CD8þCD45ROþT cells and CD8þCLAþT cells compared with peripheral blood mononuclear cells. Upon Leishmania braziliensis restimulation, most of the CD8þT 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 CD8þ 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-g, had no effect upon parasite killing. However, coculture of infected macrophages with CD4þT cells strongly increased parasite killing, which was completely reversed by anti-IFN-g. Our results reveal a dichotomy in human CL: CD8þ granzyme BþT cells mediate tissue injury, whereas CD4þIFN-gþT cells mediate parasite killing.