Research ArticleINFECTIOUS DISEASES

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

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Science Immunology  31 Aug 2018:
Vol. 3, Issue 26, eaat7668
DOI: 10.1126/sciimmunol.aat7668

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Killer trifecta

Cytotoxic granule proteins secreted by CD8+ T cells contribute to host immunity to intracellular bacterial pathogens by assisting in the killing of both infected cells and intracellular bacteria. Balin et al. studied the ability of subsets of human CD8+ T cells expressing different combinations of granule proteins to kill macrophages infected with Mycobacterium leprae. The CD8+ T cell subset with the highest efficiency of mycobacterial killing simultaneously expressed three granule proteins: granzyme B, perforin, and granulysin. Transcriptional profiling of CD8+ T cell subsets identified the NK-activating receptor NKG2C as a valuable surface marker for identification and enrichment of these potent antimicrobial CD8+ T cells. The results of this study define a specific lymphocyte subset needed for effective immune defense against human leprosy.

Abstract

Human CD8+ cytotoxic T lymphocytes (CTLs) contribute to antimicrobial defense against intracellular pathogens through secretion of cytotoxic granule proteins granzyme B, perforin, and granulysin. However, CTLs are heterogeneous in the expression of these proteins, and the subset(s) responsible for antimicrobial activity is unclear. Studying human leprosy, we found that the subset of CTLs coexpressing all three cytotoxic molecules is increased in the resistant form of the disease, can be expanded by interleukin-15 (IL-15), and is differentiated from naïve CD8+ T cells by Langerhans cells. RNA sequencing analysis identified that these CTLs express a gene signature that includes an array of surface receptors typically expressed by natural killer (NK) cells. We determined that CD8+ CTLs expressing granzyme B, perforin, and granulysin, as well as the activating NK receptor NKG2C, represent a population of “antimicrobial CTLs” (amCTLs) capable of T cell receptor (TCR)–dependent and TCR-independent release of cytotoxic granule proteins that mediate antimicrobial activity.

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