CD8(+) Granzyme B(+)-Mediated Tissue Injury vs. CD4(+)IFNγ(+)-Mediated Parasite Killing in Human Cutaneous Leishmaniasis
Santos, Claire da Silva Boaventura, Viviane Ribeiro Cardoso, Cristina Tavares, Natalia Lordelo, Morgana J Noronha, Almério Costa, Jackson Borges, Valéria M de Oliveira, Camila I Van Weyenbergh, Johan Barral, Aldina Barral-Netto, Manoel Brodskyn, Cláudia Ida # ×
Elsevier Science Pub. Co.
Journal of Investigative Dermatology vol:133 issue:6 pages:1533-40
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.Journal of Investigative Dermatology advance online publication, 14 February 2013; doi:10.1038/jid.2013.4.