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.

Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population—Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures

“…Human killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of glycoproteins that convey inhibitory or activating signals to subpopulations of NK and T lymphocytes upon recognition of their ligands, mainly HLA class I allotypes (1). In coordination with multiple other activating and inhibitory receptors for HLA class I and non-HLA molecules, KIR regulate the function of cytotoxic lymphocytes, providing them with a capacity to sense modifications of HLA expression on potential target cells (2,3). KIR repertoires expressed by NK cells of different individuals display a conspicuous phenotypic and functional diversity, genetically determined in its greatest part.…”

Cytotoxicity of Donor Natural Killer Cells to Allo-Reactive T Cells Are Related With Acute Graft-vs.-Host-Disease Following Allogeneic Stem Cell Transplantation

“…However, the specific mechanism for donor NK cells separating GVL effect from GVHD is not clear. It is worth mentioning that NK cells themselves possess the powerful function of killing leukemia cells and prevent the relapse (76).…”

Non‐KIR NK cell receptors: Role in transplantation of allogeneic haematopoietic stem cells

“…Killer‐cell immunoglobulin‐like receptors (KIRs) are principal members of this group, even though some of them also have activating properties. KIRs are a group of highly polymorphic molecules that recognize specific HLA‐A, HLA‐B and HLA‐C allotypes (Falco et al., 2019; Gao et al., 2020; Partanen et al., 2020; Thielens et al., 2012).…”

“…NK cell activation may be triggered during inflammation, for example following upregulation of stress ligands binding to activating receptors. It may also be triggered by loss of HLA class I expression, which is a hallmark of malignant lotypes (Falco et al, 2019;Gao et al, 2020;Partanen et al, 2020;Thielens et al, 2012).…”