Human antimicrobial cytotoxic T lymphocytes, defined by NK receptors and antimicrobial proteins, kill intracellular bacteria

To the Editor,

I read with keen interest the article authored by Balin S.J. et al (1) and entitled: “Human antimicrobial cytotoxic T lymphocytes, defined by NK receptors and antimicrobial proteins, kill intracellular bacteria.”

This series of experiments sought to improve understanding of patterns of granule protein expression on human CD8+ T cell subsets and their antimicrobial activity and involved human leprosy studies.

The authors of this work identified a CD8+ T cell subset capable of potent antimicrobial function and characterized by expression of the granzyme B (GZMB), perforin (PRF) and granulysin (GNLY) cytotoxic granule proteins, and NKG2C expression (surface marker for NK activating receptor) - identified by transcriptional profiling.

As outlined, PRF’s role includes penetration of the eukaryotic cell membrane, to support GZMB and GNLY entry into the cell interior. GNLY causes damage to the intracellular bacteria by binding to the bacterial membrane, while GZMB induces bacterial apoptosis and also induces the production of ROS species after subsequent cleavage of oxidative stress defense proteins (2, 3).

Of significant interest, was that the GZMB, PRF and GNLY expressing CD8+ T cell subset were present in increased frequencies in patients most resistant to infection. These CTL’s could also be expanded by IL-15 and displayed stronger antimicrobial activity than other CD8+ T cell subsets.

An important consideration includes the need to demonstrate the application of these findings to other contexts using different bacteria and parasitic organisms.

Overall an exciting series of results highlighting the collaborative role of three cytotoxic granule molecules GZMB, PRF and GNLY, and NKG2C expression in equipping amCTL’s (antimicrobial CTL’s) to enable killing of intracellular bacteria such as M Leprae and L monocytogenes.

Respectfully yours,

Dr Dianne Sika-Paotonu C.Q.S.
Associate Dean (Pacific)
Senior Lecturer, Pathology & Molecular Medicine
Wellington School of Medicine and Health Sciences, University of Otago, New Zealand
Honorary Research Associate, Telethon Kids Institute, Australia
Honorary Research Associate, Victoria University of Wellington, New Zealand
Affiliate Investigator Maurice Wilkins Centre for Molecular Biodiscovery
University of Auckland, New Zealand

References:
1. Balin SJ, Pellegrini M, Klechevsky E, Won ST, Weiss DI, Choi AW, Hakimian J, Lu J, Ochoa MT, Bloom BR, Lanier LL. Human antimicrobial cytotoxic T lymphocytes, defined by NK receptors and antimicrobial proteins, kill intracellular bacteria. Science immunology. 2018 Aug 31;3(26):eaat7668.

2. Walch M, Dotiwala F, Mulik S, Thiery J, Kirchhausen T, Clayberger C, Krensky AM, Martinvalet D, Lieberman J. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell. 2014 Jun 5;157(6):1309-23.

3. Dotiwala F, Mulik S, Polidoro RB, Ansara JA, Burleigh BA, Walch M, Gazzinelli RT, Lieberman J. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nature medicine. 2016 Feb;22(2):210.