NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses

Abstract

The negative regulation of adaptive immunity is relevant to maintain lymphocyte homeostasis. Several studies on natural killer (NK) cells have shown a previously unappreciated immunomodulatory role, as they can negatively regulate T cell-mediated immune responses by direct killing and by secretion of inhibitory cytokines. The molecular mechanisms of T cell suppression by NK cells, however, remained elusive. Only in the last few years has it become evident that, upon activation, human T cells express MICA–B, ULBP1–3, and PVR, ligands of the activating receptors NKG2D and DNAM-1, respectively. Their expression renders T cells targets of NK cell lysis, representing a new mechanism taking part to the negative regulation of T cell responses. Studies on the expression of NKG2D and DNAM-1 ligands on T cells have also contributed in understanding that the activation of ATM (ataxia-telangiectasia, mutated)/ATR (ATM/Rad3-related) kinases and the DNA damage response is a common pathway regulating the expression of activating ligands in different types of cells and under different conditions. The functional consequences of NKG2D and DNAM-1 ligand expression on activated T cells are discussed in the context of physiologic and pathologic processes such as infections, autoimmunity, and graft versus host disease.

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

“…3C) cells were also found in this subset. Characterization of different activating NK-cell receptors suggested to be involved in NK cellmediated immune regulation of activated T cells (39) revealed that on the MS cell surface, expression of DNAM-1 was significantly reduced on both NK-cell subsets, whereas no differences in the NK-cell surface expression of NKG2D was observed (Fig. 3B).…”

Recognition of Tumors by the Innate Immune System and Natural Killer Cells

“…Interestingly, certain untransformed cells undergoing rapid proliferation, such as early embryonic brain cells and cells proliferating in healing skin wounds, were found to express RAE-1 in vivo (Jung et al, 2012). Earlier studies showed that proliferating human T-cells upregulate NKG2D ligands (Zingoni et al, 2012), and several reports have described constitutive NKG2D ligand expression in subpopulations of cells in rapidly proliferating tissues such as the bone marrow (Ogasawara et al, 2005) and intestinal epithelium (Groh et al, 1996). On the other hand, proliferation is frequently insufficient to result in substantial upregulation of NKG2D ligands.…”

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…MSC can bear ligands for surface molecules involved either in the activation or inhibition of lymphocyte functions [2,3]. Indeed, DNAX accessory molecule 1 (DNAM-1) can react with MSC-expressing polio virus receptor (PVR, CD155) and nectin 2 (CD112),which are two DNAM-1Ls [36,37]. This recognition should usually lead to killing of the DNAM-1L-bearing cell [36,37].…”

“…Indeed, DNAX accessory molecule 1 (DNAM-1) can react with MSC-expressing polio virus receptor (PVR, CD155) and nectin 2 (CD112),which are two DNAM-1Ls [36,37]. This recognition should usually lead to killing of the DNAM-1L-bearing cell [36,37]. However, it is also possible that DNAM-1L can bind T cell immunoglobulin and ITIM domain (TIGIT) or CD96 inhibitory molecules on lymphocytes, leading to the impairment of immune response [38].…”