Granzyme B Produced by Natural Killer Cells Enhances Inflammatory Response and Contributes to the Immunopathology of Cutaneous Leishmaniasis

• Published in: The Journal of infectious diseases Vol. 221; no. 6; pp. 973 - 982
• Main Authors: Campos, Taís M, Novais, Fernanda O, Saldanha, Maíra, Costa, Rúbia, Lordelo, Morgana, Celestino, Daniela, Sampaio, Camilla, Tavares, Natália, Arruda, Sérgio, Machado, Paulo, Brodskyn, Cláudia, Scott, Phillip, Carvalho, Edgar M, Carvalho, Lucas P
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 02.03.2020
• Subjects: Case-Control Studies; CD4-Positive T-Lymphocytes; CD8 antigen; Cutaneous leishmaniasis; Cytotoxicity; Gene Expression Regulation, Enzymologic - immunology; Granzyme B; Granzymes - genetics; Granzymes - metabolism; Humans; Inflammation; Inflammation - metabolism; Interferon-gamma - genetics; Interferon-gamma - metabolism; Killer Cells, Natural - enzymology; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - pathology; Lymphocytes T; Major and Brief Reports; Natural killer cells; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Parasitic diseases; Perforin; Perforin - genetics; Perforin - metabolism; Peripheral blood; Skin diseases; Skin lesions; T-Lymphocytes, Cytotoxic; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; γ-Interferon; granzyme B; NK cells; cytotoxic activity; T cells; cutaneous leishmaniasis; CD8; CD8+ T cells
• DOI: 10.1093/infdis/jiz538
• ISSN: 0022-1899; 1537-6613

Abstract Background Skin lesions from patients infected with Leishmania braziliensis has been associated with inflammation induced by cytotoxic CD8+ T cells. In addition, CD8+ T cell-mediated cytotoxicity has not been linked to parasite killing. Meanwhile, the cytotoxic role played by natural killer (NK) cells in cutaneous leishmaniasis (CL) remains poorly understood. Methods In this study, we observed higher frequencies of NK cells in the peripheral blood of CL patients compared with healthy subjects, and that NK cells expressed more interferon-γ, tumor necrosis factor (TNF), granzyme B, and perforin than CD8+ T cells. Results We also found that most of the cytotoxic activity in CL lesions was triggered by NK cells, and that the high levels of granzyme B produced in CL lesions was associated with larger lesion size. Furthermore, an in vitro blockade of granzyme B was observed to decrease TNF production. Concclusions Our data, taken together, suggest an important role by NK cells in inducing inflammation in CL, thereby contributing to disease immunopathology. Our data show a key role for NK cells in the immunopathology observed in cutaneous leishmaniasis patients. Granzyme B, produced mainly by these cells, induces proinflammatory cytokines and is associated with lesion size.