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

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.status: publishe

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

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2013-10-24T14:12:11Z No. of bitstreams: 1 Claire SS CD8+ granzyme b...pdf: 4914876 bytes, checksum: e54c8737a502be3105cd578fa7d10ef4 (MD5)Made available in DSpace on 2013-10-24T14:12:11Z (GMT). No. of bitstreams: 1 Claire SS CD8+ granzyme b...pdf: 4914876 bytes, checksum: e54c8737a502be3105cd578fa7d10ef4 (MD5) Previous issue date: 2013Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade de São Paulo. Faculdade de Ciências Farmacêuticas. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas . São Paulo, SP, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Instituto de Investigação em Imunologia. São Paulo, SP, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Instituto de Investigação em Imunologia. São Paulo, SP, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Instituto de Investigação em Imunologia. São Paulo, SP, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilUniversidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilA 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