NKp44 and Natural Cytotoxicity Receptors as Damage-Associated Molecular Pattern Recognition Receptors

Abstract

Natural killer (NK) cells are a key constituent of the innate immune system, protecting against bacteria, virally infected cells, and cancer. Recognition and protective function against such cells are dictated by activating and inhibitory receptors on the surface of the NK cell, which bind to specific ligands on the surface of target cells. Among the activating receptors is a small class of specialized receptors termed the natural cytotoxicity receptors (NCRs) comprised of NKp30, NKp46, and NKp44. The NCRs are key receptors in the recognition and termination of virally infected and tumor cells. Since their discovery over 10 years ago, ligands corresponding to the NCRs have largely remained elusive. Recent identification of the cellular ligands for NKp44 and NKp30 as exosomal proliferating cell nuclear antigen (PCNA) and HLA-B-associated transcript 3 (BAT3), respectively, implicate that NCRs may function as receptors for damage-associated molecular pattern (DAMP) molecules. In this review, we focus on NKp44, which surprisingly recognizes two distinct ligands resulting in either activation or inhibition of NK cell effector responses in response to tumor cells. The inhibitory function of NKp44 requires further study as it may play a pivotal role in placentation in addition to being exploited by tumors as a mechanism to escape NK cell killing. Finally, we suggest that the NCRs are a class of pattern recognition receptors, which recognize signals of genomic instability and cellular stress via interaction with the c-terminus of DAMP molecules localized to the surface of target cells by various co-ligands.

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

“…To note, we found an overexpression of NKp44 that might seem contrary to what would be expected for an activating receptor but this upregulation was also observed in breast and lung cancer (12,14), and seems rather be a hallmark of NK cell activation. Interestingly, it has been recently described that NKp44 recognizes two distinct ligands resulting in either activation or inhibition of NK cell effector responses in response to tumor cells (40). Our study provides evidence for the importance of NKp46 and NKG2D in human prostate cancer.…”

Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

“…Cellular ligands for NCR have remained elusive for a long time. Recently, proliferating cell nuclear antigen (PCNA) has been identified as an NKp44 ligand and HLA-B-associated transcript 3 (BAT3), B7-H6 and CMV pp65 tegument protein as NKp30 ligands suggesting that the NCRs are a class of pattern recognition receptors recognizing damage-associated molecular patterns related to cellular stress [27,35].…”

Coevolution of MHC genes (LMP/TAP/class Ia, NKT‐class Ib, NKp30‐B7H6): lessons from cold‐blooded vertebrates

“…NCRs recognize virus‐derived molecules such as HA from influenza, glycoprotein from vaccinia virus, and pp65 from HCMV . They also bind to self molecules such as BAT3 [also known as BAG6 ] and PCNA . Binding to ligands relays activating signals via ITAM‐containing adapter molecules (e.g.…”

“…CD3ζ) associated in the cytoplasmic regions . NKp44 and NKp30 are also associated with DAMPs, which are often upregulated in cancer cells . B7H6 is one of the known ligands for NKp30 which becomes upregulated in transformed cancer cells , and engagement of B7H6‐NKp30 activates NK cells to kill B7H6‐expressing transformed cells.…”