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

J Infect Dis. 2020 Mar 2;221(6):973-982. doi: 10.1093/infdis/jiz538.

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.

Keywords: CD8+ T cells; NK cells; cutaneous leishmaniasis; cytotoxic activity; granzyme B.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CD4-Positive T-Lymphocytes
  • Case-Control Studies
  • Gene Expression Regulation, Enzymologic / immunology*
  • Granzymes / genetics
  • Granzymes / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / enzymology*
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / pathology*
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Perforin / genetics
  • Perforin / metabolism
  • T-Lymphocytes, Cytotoxic
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Tumor Necrosis Factor-alpha
  • Perforin
  • Interferon-gamma
  • GZMB protein, human
  • Granzymes