NK cell function is closely regulated by numerous inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. NKp44, originally discovered as an activating NK cell receptor, was recently found to elicit inhibitory effects on NK cell effector function through recognition of cell surface PCNA. Other reports have pointed to potential associations between NKp44 and HLA I molecules, as well as HLA I and Damage Associated Molecular Pattern molecules (DAMPs) on the surface of tumor cells. In this report, we have identified novel interaction between HLA I and PCNA on the surface of human tumor cells by confocal microscopy and immunoprecipitation. In addition to previous reports, we show PCNA on the cell surface where novel association with HLA I does not require the presence of NKp44 expressing NK cells and occurs with endogenous PCNA. The association of HLA I and PCNA forms the inhibitory ligand for NKp44, resulting in inhibition of NK cell cytotoxicity. We further postulate NCR ligands are composed of DAMP molecules localized to the cell surface, colocalizing with HLA I, and potentially heparin sulfate proteoglycans.

Our study demonstrated that CS1 plays an inhibitory role in human monocytes to control proinflammatory immune responses.

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.

Cytotoxic T cells play a critical role in the control of HIV and the progression of infected individuals to AIDS. 2B4 (CD244) is a member of the SLAM family of receptors that regulate lymphocyte development and function. The expression of 2B4 on CD8 + T cells was shown to increase during AIDS disease progression. However, the functional role of 2B4 + CD8 + T cells against HIV infection is not known. Here, we have examined the functional role of 2B4 + CD8 + T cells during and after stimulation with HLA B14 or B27 restricted HIV epitopes. Interestingly, IFN-γ secretion and cytotoxic activity of 2B4 + CD8 + T cells stimulated with HIV peptides were significantly decreased when compared to influenza peptide stimulated 2B4 + CD8 + T cells. The expression of the signaling adaptor molecule SAP was downregulated in 2B4 + CD8 + T cells upon HIV peptide stimulation. These results suggest that 2B4 + CD8 + T cells play an inhibitory role against constrained HIV epitopes underlying the inability to control the virus during disease progression.

Abstract:Review on NCR2, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

NK cell functions are regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. In order to establish and grow, cancer cells must escape NK cell-mediated killing. By altering the expression of ligands for NK cell receptors (down-regulating activating ligands and up-regulating inhibitory ligands) cancer cells may evade NK mediated killing. Here we have examined the expression of LLT1 (Lectin-like transcript-1 or CLEC2D), a ligand for the NK cell inhibitory receptor NKRP1A (CD161) as well as proliferating cell nuclear antigen (PCNA), a ligand for NKp44 on surface of prostate cancer cell DU145. Expression of LLT1 on DU145 cell inhibited NK cell cytolytic activity though NKRP1A (CD161). Similarly, expression of exosomal PCNA by DU145 inhibited NK cell cytotoxicity through NKp44. The association of HLA I and PCNA on DU145 forms an inhibitory ligand for NKp44. Blocking the inhibitory signals by anti-LLT1 and anti-NKp44 monoclonal antibodies enhanced the killing of prostate cancer cells by NK cells. Thus tumor cells may use multiple pathways to inhibit NK effector function and combinatorial targeting of these pathways could lead to efficient elimination of cancer cells.

No abstract

Natural Killer (NK) cell function is strictly regulated by inhibitory and activating receptors binding corresponding ligands on the surface of target cells, providing vital first line defenses against infections and cancer. NKp44, originally discovered as an activating NK cell receptor, was recently found to elicit inhibitory effects on NK cell effector function through recognition of cell surface Proliferation Cell Nuclear Antigen (PCNA). Other reports have pointed to potential associations between NKp44 and Human Leukocyte Antigen (HLA) I molecules. In this report, we have identified novel interactions between HLA I and PCNA on the surface of human tumor cells by confocal microscopy and immunoprecipitation. In addition to previous reports, we show PCNA on the cell surface where novel association with HLA I does not require the presence of NKp44 expressing NK cells and occurs with endogenous PCNA. The association of HLA I and PCNA forms the inhibitory ligand for NKp44, resulting in inhibition of NK effector function. Furthermore, extracellular PCNA was only found on tumor cells exhibiting a cancer stem cell phenotype. Thus extracellular PCNA is a novel marker for cancer stem cells, derived from conventional growth of tumor epithelial cell lines in tissue culture, and a mechanism by which cancer stem cells evade NK cell effector functions.