Natural killer cells: From surface receptors to the cure of high-risk leukemia (Ceppellini Lecture)

Abstract

Natural killer (NK) cells are innate immune effector cells involved in the first line of defense against viral infections and malignancies. In the last three decades, the identification of HLA class I-specific inhibitory killer immunoglobulin-like receptors (KIR) and of the main activating receptors has strongly improved our understanding of the mechanisms regulating NK cell functions. The increased knowledge on how NK cells discriminate healthy cells from damaged cells has made it possible to transfer basic research notions to clinical applications. Of particular relevance is the strong NK-mediated anti-leukemia effect in haploidentical hematopoietic stem cell transplantation to cure high-risk leukemia.

Keywords: HLA class I; NK alloreactivity; NK cells; activating NK receptors; acute high-risk leukemia; hematopoietic stem cell transplantation; inhibitory checkpoints; killer immunoglobulin-like receptors.

Figure 1

Natural killer (NK)‐mediated lysis in autologous and allogeneic settings. NK cells express inhibitory and activating receptors allowing to finely tune NK‐mediated cytotoxicity. A, In an autologous setting, NK cells spare healthy cells expressing HLA class I molecules whereas lyse autologous cells that, upon viral infection or tumor transformation, down‐regulate/loose HLA class I molecules or up‐regulate stress induced molecules. B, In an allogeneic setting, such as hematopoietic stem cell transplantation, donor NK cells expressing inhibitory receptor that recognize self‐HLA class I allotype not present on patient cells display alloreactivity