Cytokine-induced memory-like natural killer cells

TLDR

The innate immune system, including natural killer (NK) cells, traditionally lacks memory, whereas adaptive immune cells possess antigen‑specific memory, prompting investigation into NK cell memory potential. Cytokine‑activated NK cells persist in naïve hosts for 7–22 days, remain phenotypically naive, yet produce markedly more IFN‑γ upon restimulation, demonstrating intrinsic memory without enhanced cytotoxicity.

Abstract

The mammalian immune response to infection is mediated by 2 broad arms, the innate and adaptive immune systems. Innate immune cells are a first-line defense against pathogens and are thought to respond consistently to infection, regardless of previous exposure, i.e., they do not exhibit memory of prior activation. By contrast, adaptive immune cells display immunologic memory that has 2 basic characteristics, antigen specificity and an amplified response upon subsequent exposure. Whereas adaptive immune cells have rearranged receptor genes to recognize the universe of antigens, natural killer (NK) cells are innate immune lymphocytes with a limited repertoire of germ-line encoded receptors for target recognition. NK cells also produce cytokines such as IFN-gamma (IFN-gamma) to protect the host during the innate response to infection. Herein, we show that cytokine-activated NK cells transferred into naïve hosts can be specifically detected 7-22 days later when they are phenotypically similar to naïve cells and are not constitutively producing IFN-gamma. However, they produce significantly more IFN-gamma when restimulated. This memory-like property is intrinsic to the NK cell. By contrast, memory-like NK cells do not express granzyme B protein and kill targets similarly to naïve NK cells. Thus, these experiments identify an ability of innate immune cells to retain an intrinsic memory of prior activation, a function until now attributed only to antigen-specific adaptive immune cells.