DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK–T cell interaction

Abstract

IntroductionIn addition to their role in providing antitumor and antiviral immunity, 1 natural killer (NK) cells are also able to regulate the T-cell arm of the adaptive immune response by secreting different cytokines and chemokines. 2 Moreover, several studies have provided evidence of cognate cell-cell interactions between NK cells and various leukocyte types, including dendritic cells (DCs) and B and T lymphocytes. [3][4][5] Although NK cells have been thought to mainly promote adaptive immune responses, recent in vivo studies suggest that they can also restrain T cell-mediated immune responses. Therefore, the depletion of NK cells results in enhanced T-cell proliferation and effector functions during murine cytomegalovirus infection 6 and in an antitumor response against lymphoma cells. 7 Conversely, several studies have indicated that the depletion of NK cells is associated with increased severity of autoimmune diseases. In fact, NK cell-depleted mice develop a more severe form of experimental autoimmune encephalomyelitis, 8 and NK-cell-mediated downregulation of autoreactive cytotoxic T lymphocytes has been shown to have a protective role in type 1 diabetes. 9 These findings suggest that NK cells may be crucial for terminating T cell-mediated responses and for preventing inappropriate T-cell activation and effector functions leading to the development of autoimmune diseases.NK cell-mediated attenuation of T-cell responses can involve several mechanisms, including the production of inhibitory cytokines (eg, TGF-␤ and IL-10) 10,11 and killing of DCs and/or activated T cells. 4,12,13 In regard to the NK cell-mediated killing of T cells, IL-2-activated mouse and human NK cells recognize and lyse T-cell blasts in a perforin-dependent manner through the activating receptor NKG2D. 4,12 Interestingly, the results of our previous study indicated that Ag stimulation of human T cells was sufficient to induce the surface expression of the NKG2D ligands (NKG2DLs) MHC class I-related chain A (MICA), MICB, and UL16-binding proteins 1-3 (ULBP1-3). 4,14 To date, little is known about the existence of additional receptor-ligand interactions that might contribute to the NK cell-mediated recognition of T lymphocytes.DNAX accessory molecule-1 (DNAM-1) is an activating receptor belonging to the Ig superfamily that is constitutively expressed by most NK cells, T cells, macrophages, and DCs. 15,16 DNAM-1 interacts with lymphocyte function-associated antigen 1 (LFA-1), and this association is required for its functional activity on both NK and cytotoxic T cells. 17 Ligands for DNAM-1 (DNAM1Ls) include Nectin-2 and poliovirus receptor (PVR), which belong to the Nectin/Nectin-like family of adhesion molecules. 18 DNAM1Ls are often expressed by tumor cells and can activate or enhance tumor cell lysis in vitro. 15,18 Recent studies have reported that they can also be expressed by monocytes, DCs, and phytohemagglutinin (PHA)-stimulated CD4 ϩ T lymphocytes. 19,20 Little information is available about the molecular mechanisms regulating...

Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

“…Also, productive infection of cells with the gammaherpesvirus Epstein-Barr virus is associated with up-regulation of the DNAM-1 ligand CD112 (25). Although the underlying mechanism of such virus-induced cellular response remains to be investigated, the cellular DNA damage response (DDR) may play a role, as many viruses, including herpesviruses and retroviruses, activate the DDR, and DDR activation has been reported to trigger DNAM-1 ligand up-regulation (26,(36)(37)(38).…”

Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells

“…33 As expected, the intensity of Nec-2 and PVR expression was inversely correlated, Nec-2 being expressed in almost 100% of cases and PVR being virtually absent, unlike, for example, superantigen-stimulated T cells which at the cell surface express only PVR with a mechanism involving a DNA-damage responsedependent pathway. 40 Our methodological approach used for NK cell enrichment and expansion, which is essential to obtain a sufficient number of effectors to pursue a program of adoptive cellular therapy, may be transferred into the clinic for experimental phase I/II studies based on the in vivo infusion of ex vivo expanded and activated NK cells for the control of MRD in ALL patients. The possible correlation between the intensity of expression of ligands for NK cell activating receptors and the susceptibility to lysis may help identify patients who may gain the most benefit from NK-based immunotherapy and from alloreactive donors in the context of haploidentical HSCT.…”

Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression

“…To gain insights into the molecular mechanisms regulating the expression of activating ligands in infected cells, we investigated the role of DDR, a host cell pathway that positively affects the expression of activating ligands (35)(36)(37)(38)(39)(40)(41)(42)(43) and that it is activated by HCMV (26,27,(29)(30)(31)(32)(33)(34). Nevertheless, in HCMV-infected HFFs, MICA, ULBP3, and PVR were still increased even when ATM, ATR, and/or DNA-PK were knocked down, thus indicating that these DDR kinases are not involved in the HCMV-mediated ligand stimulation, similar to what has been reported for murine NKG2DL during murine CMV infection (78).…”

“…As previous studies reported that HCMV manipulates the DDR (26,27,(29)(30)(31)(32)(33)(34), a pathway able to stimulate NKG2DL and DNAM-1L expression as well (35)(36)(37)(38)(39)(40)(41)(42)(43), we examined the involvement of DDR signaling in the HCMV-mediated upregulation of activating ligands using genetic and pharmacological approaches.…”

“…DDR is activated by many viruses, including HCMV, and although its functional relevance in HCMV infection has not been clarified, this virus induces DDR, including activation of ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR), and the downstream protein H2AX (26,27,(29)(30)(31)(32)(33)(34). Interestingly, expression of some NKG2DL and DNAM-1L can be dependent on the activation of DDR and on ATM/ATR kinases (35)(36)(37)(38)(39)(40)(41)(42)(43).…”