Role of TNF superfamily ligands in innate immunity

Abstract

Natural killer (NK) cells and dendritic cells (DCs) are essential effector cells of the innate immune system that rapidly recognize and eliminate microbial pathogens and abnormal cells, and induce and regulate adaptive immune functions. While NK cells express perforin and granzymes in the lysosomal granules and transmembrane tumor necrosis factor superfamily ligands (tmTNFSFL) on the plasma membrane, DCs express only tmTNFSFL on the plasma membrane. Perforin and granzymes are cytolytic molecules, which NK cells use to mediate a secretory/necrotic killing mechanism against rare leukemia cell targets. TNFSFL are pleiotropic transmembrane molecules, which can mediate a variety of important functions such as apoptosis, development of peripheral lymphoid tissues, inflammation and regulation of immune functions. Using tmTNFSFL, NK cells and DCs mediate a cell contact-dependent non-secretory apoptotic cytotoxic mechanism against virtually all types of cancer cells, and cross talk that leads to polarization and reciprocal stimulation and amplification of Th1 type cytokines secreted by NK cells and DCs. In this paper, we review and discuss the supporting evidence of the non-secretory, tmTNFSFL-mediated innate mechanisms of NK cells and DCs, their roles in anticancer immune defense and potential of their modulation and use in prevention and treatment of cancer.

Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2β (Group VIA Phospholipase A2)

“…PLA 2 Expression in Macrophages-PLA 2 s are ubiquitously expressed and activated in inflammatory settings (17,37,38), and as expected, iPLA 2 ␤ and cPLA 2 mRNA species increase during macrophage differentiation from their bone marrowderived precursors (Fig. 1A).…”

“…1B), iPLA 2 ␥ (Fig. 1C), and cPLA 2 (Fig. 1D) are evident in already differentiated WT naïve peritoneal FIGURE 1.…”

“…The abbreviations used are: PGE 2 , prostaglandin E 2 ; T1D, type 1 diabetes; T2D, type 2 diabetes; PLA 2 , phospholipase A 2 ; ALOX12, 12-lipoxygenase (12-LO); CCL2, monocyte chemoattractant protein-1; CCL5, C-C motif chemokine 5 precursor; CDC, cinnamyl-3,4-dihydroxy-␣-cyanocinnamate; CD68, cluster of differentiation; CHIL3, chitinase-like3 (YM1); CXCL10, chemokine (C-X-C motif) ligand 10; COX, cyclooxygenase; iNOS, inducible nitric oxide; cPLA 2 , cytosolic phospholipase A 2 ; iPLA 2 ␤, group VIA phospholipase A 2 ␤; iPLA 2 ␥, group VIA phospholipase A 2 ␥; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPS, lipopolysaccharide; MRC1, mannose receptor 1c type precursor; NF-B1, nuclear factor -light chain enhancer of activated B-cells (NF-B p105, p50 precursor); NOD, nonobese diabetic; NOX4, NADPH oxidase 4; PTGS2, mouse cyclooxygenase 2 (COX2); RT-qPCR, real time quantitative PCR; RELA, Rel-associated protein (NF-B p65); ROS, reactive oxygen species; S-BEL, S-enantiomer of bromoenol lactone; STAT1 and STAT6, signal transducer and activator of transcription 1 and 6, respectively; Arg, arginase.…”

Tumor Necrosis Factor-α 238 G/A Polymorphism and Risk of Hepatocellular Carcinoma: Evidence from a Meta-analysis

“…TNF-α is produced by many types of cells, such as macrophages, neutrophils, fibroblasts, keratinocytes, NK cells, T and B cells, and tumour cells (Mocellin et al, 2008;Vujanovic, 2011;Sun, 2012). TNF-α is a potent pleiotropic proinflammatory cytokine that affects cell growth, cell differentiation, cellular function and survival (Mocellin et al, 2008;Sun, 2012).…”

Contact-dependent Signaling

“…68 Transmembrane TNF and transmembrane Fas ligand induce apoptosis in cancer cells, while their soluble ligands are weakly cytotoxic or block apoptosis mediated by the corresponding transmembrane ligands. 69 In addition, membrane-bound Fas ligand induces inflammation, while soluble Fas ligand suppresses it. 69 Since membrane-anchored growth factors can have their own specific activities, shedding must be tightly regulated.…”