Regulation of CR3 (CD11b/CD18)-dependent natural killer (NK) cell cytotoxicity by tumour target cell MHC class I molecules

Abstract

SUMMARYPhagocyte and NK cell CR3 functions as both an adhesion molecule and an iC3b receptor mediating cytotoxic responses to microorganisms. Cytotoxic activation of iC3b receptor function requires ligation of both a CD11b I-domain site for iC3b and a lectin site located in the C-terminus of CD11b. Because tumours lack the CR3-binding polysaccharides of bacteria and fungi, iC3b-opsonized tumours do not stimulate CR3-dependent cytotoxicity. Previous studies showed that NK cells could be induced to kill iC3b-opsonized tumours with small soluble b-glucans that bound with high affinity to CR3, bypassing the absence of similar polysaccharides on tumour membranes. Because CR3 signalling requires several tyrosine phosphorylation events, it appeared possible that CR3-dependent killing of autologous tumour cells might be suppressed by NK cell inhibitory receptors for MHC class I (KIR and CD94/NKG2) whose action involves recruitment of SHP-1 and SHP-2 tyrosine phosphatases. In the current study, Epstein-Barr virus (EBV)-transformed B cells were used as targets following opsonization with iC3b. Soluble b-glucan primed CR3 for killing of iC3b-coated B cells, but autologous class I-bearing targets were 84% more resistant than class I-deficient Daudi cells. Blockade of target cell class I with a MoAb specific for a domain recognized by both KIR and CD94/NKG2 resulted in comparable killing of class I þ B cells. By contrast, another MoAb to class II had no effect on cytotoxicity. These data suggest that NK cell recognition of class I suppresses CR3/tyrosine kinase-dependent cytotoxicity in the same way as it suppresses cytotoxicity mediated by other tyrosine kinase-linked receptors such as FcgRIIIA (CD16).

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

“…Indeed, NK cells can lyse tumor cells after the recruitment of complement receptor 3 (CR3) by iC3b, especially when MHC class I molecules are poorly expressed. 45 NeuT C tumor cells are susceptible to the activity of NK cells, as an inverse correlation exists between the expression levels of neuT protein and those of MHC class I molecules as well as other components of the antigen-processing machinery. 46 Moreover, signaling through the Her2/Her3 pathway in breast tumor cell lines has been shown to enhance their recognition by NK and T cells thanks to the killer cell lectin-like receptor subfamily K, member 1 (KLRK1, or NKG2D).…”

Yeast β-Glucan Amplifies Phagocyte Killing of iC3b-Opsonized Tumor Cells via Complement Receptor 3-Syk-Phosphatidylinositol 3-Kinase Pathway

“…Previously published in vitro experiments suggested that small molecular mass soluble ␤-glucans mediated neutrophil, M, and NK cell CR3-dependent cellular cytotoxicity of iC3b-opsonized tumors (25,33,34). Many of these small molecular mass soluble ␤-glucans demonstrated in vivo efficacy, but were observed to have very brief in vivo t 1/2 , thus requiring daily i.v.…”

Human Thy‐1 induces secretion of matrix metalloproteinase‐9 and CXCL8 from human neutrophils

“…First, it is an adhesion molecule mediating the diapedesis of neutrophils through endothelium [1]. Secondly, being a complement receptor (CR3) it mediates and supports phagocytosis of pathogens and further regulates the degranulation response to microorganisms [1,[33][34][35]. However, it is important that cytotoxic agents from neutrophil granules are not released until neutrophils have migrated into the extracellular tissue to the site of infection.…”