CD8+ granzyme B+ -mediated tissue injury vs. CD4 + IFNγ+ -mediated parasite killing in human cutaneous leishmaniasis

Abstract

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. © 2013 The Society for Investigative Dermatology.