Human Natural Killer Receptors, Co‐Receptors, and Their Ligands

Abstract

In the last 20 years, the study of human natural killer (NK) cells has moved from the first molecular characterizations of very few receptor molecules to the identification of a plethora of receptors displaying surprisingly divergent functions. We have contributed to the description of inhibitory receptors and their signaling pathways, important in fine regulation in many cell types, but unknown until their discovery in the NK cells. Inhibitory function is central to regulating NK-mediated cytolysis, with different molecular structures evolving during speciation to assure its persistence. More recently, it has become possible to characterize the NK triggering receptors mediating natural cytotoxicity, unveiling the existence of a network of cellular interactions between effectors of both natural and adaptive immunity. This unit reviews the contemporary history of molecular studies of receptors and ligands involved in NK cell function, characterizing the ligands of the triggering receptor and the mechanisms for finely regulating their expression in pathogen-infected or tumor cells. © 2018 by John Wiley & Sons, Inc.

Inherited defects in natural killer cells shape tumor immune microenvironment, clinical outcome and immunotherapy response

“…In general, an excess of activating over inhibitory signals triggers the production and release of effector molecules, which can lead to the death of the infected or transformed cancer cell ( 22 ). Thus, to further explore the association between NK cell inherited defects with cancer progression and metastasis, we compiled a comprehensive set of NK cell genes including NK cell receptors and ligands, genes in NK cell signaling pathways (i.e., KEGG NK cell-mediated cytotoxicity pathway ( 23, 24, 25 ), and then conducted Fisher’s tests to identify genes which had significantly differential frequencies between TIME-rich group and TIME-poor/-intermediate group. For a given cancer type, we found 15-20 defected NK cell genes which had significantly higher frequencies in TIME-poor/-intermediate group than TIME-rich group (FDR-corrected p <0.25).…”

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

“…The principal NKG2D ligands are the stress‐inducible non‐classical molecules MHC class I polypeptide‐sequence A (MICA) and B (MICB) (Bauer et al., 1999). MICA and MICB are highly polymorphic, and at least 104 MICA and 42 MICB alleles are known (Biassoni & Malnati, 2018). NKG2D can also bind certain other ligands, such as protein from the UL16‐binding protein (ULBP) family (Bacon et al, 2004).…”

“…NKp46, NKp44 and NKp30 were thought to bind to the membrane‐associated heparin sulphate proteoglycans (HSPGs), although this was not confirmed for NKp30 by a later study (Bloushtain et al, 2004; Warren et al, 2005). Furthermore, this could be indirect in the case of NKp46, as HSPGs are bound to another NKp46 ligand, vimentin (Biassoni & Malnati, 2018; Garg et al, 2006). Vimentin is a human protein which is upregulated in monocytes infected by M. tuberculosis , and its binding to NKp46 induces NK cell‐mediated lysis of these infected monocytes (Garg et al, 2006).…”

“…They are encoded by the genes LILRB1 , LILRB4 , LILRB2, respectively, all of them located on chromosome 19. As they can potentially suppress T‐cell responses and proliferation, they are thought to have a role in allograft tolerance during transplantation and cancer (Biassoni & Malnati, 2018; Brown et al., 2009). Both ILT2 and ILT4 recognize the non‐classical HLA‐G and HLA‐F molecules, while ILT2 also recognizes other class I MHC (Chapman et al., 1999; Lepin et al., 2000).…”

“…MICA and MICB are highly polymorphic, and at least 104 MICA and 42 MICB alleles are known (Biassoni & Malnati, 2018). NKG2D…”