Natural killer cell biology: an update and future directions

Abstract

Natural killer (NK) cells constitute a minor subset of normal lymphocytes that initiate innate immune responses toward tumor and virus-infected cells. They can mediate spontaneous cytotoxicity toward these abnormal cells and rapidly secrete numerous cytokines and chemokines to promote subsequent adaptive immune responses. Significant progress has been made in the past 2 decades to improve our understanding of NK cell biology. Here we review recent discoveries, including a better comprehension of the "education" of NK cells to achieve functional competence during their maturation and the discovery of "memory" responses by NK cells, suggesting that they might also contribute to adaptive immunity. The improved understanding of NK cell biology has forged greater awareness that these cells play integral early roles in immune responses. In addition, several promising clinical therapies have been used to exploit NK cell functions in treating patients with cancer. As our molecular understanding improves, these and future immunotherapies should continue to provide promising strategies to exploit the unique functions of NK cells to treat cancer, infections, and other pathologic conditions.

Keywords: ADCC; AML; Acute myeloid leukemia; Antibody-dependent cellular cytotoxicity; CAR; Chimeric antigen receptor; Class I MHC; HSC; Hematopoietic stem cell; IFN-γ; ILC; ITIM; Immunoreceptor tyrosine-based inhibitory motif; Innate lymphoid cell; KIR; Killer cell immunoglobulin-like receptor; MCMV; MHC-I; MM; Mouse cytomegalovirus; Multiple myeloma; NCR; NK; Natural cytotoxicity receptor; Natural killer; Natural killer cell; PD-1; Programmed cell death 1; SRIR; Self-recognizing inhibitory receptor; antibody-dependent cellular cytotoxicity; cancer; hematopoietic stem cell transplantation; immune memory; immunomodulatory drugs; innate immunity; killer cell immunoglobulin-like receptors; viral infection.

Figure 1. Models of NK cell education

During NK cell development, only some of the stochastically-expressed inhibitory receptors (KIR in humans and Ly49 in mice) recognize self MHC-I ligand (self-recognizing inhibitory receptor; SRIR). SRIR interactions promote NK cell education to mediate cytotoxicity toward an abnormal cell that has lost expression of MHC-I, whereas a mature NK cell expressing only unliganded inhibitory receptors becomes hyporesponsive. Models of NK cell education are indicated: 1) Rheostat: expression of >1 SRIR promotes more robust education, 2) Cis Interaction: interactions between SRIR and MHC-I on the NK cell surface are important, 3) Arming: inhibitory signaling blocks chronic activation signals that would otherwise anergize (“Disarming”); 4) Licensing: an ITIM-mediated signal drives education.