NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies

Abstract

IntroductionHuman cytomegalovirus (HCMV) infection is highly prevalent in healthy persons and the virus remains in a lifelong latent state, undergoing occasional reactivation and causing an important morbidity in immunocompromised patients. 1 An effective defense against CMV infection requires the participation of both T and NK cells. 2 To escape T cell-mediated recognition, CMV interferes with the expression of major histocompatibility complex molecules and antigen presentation. 3 The loss of human leukocyte antigen (HLA) class I molecules in infected cells impairs the engagement of inhibitory receptors, thus promoting the activation of NK-cell effector functions. Reciprocally, the virus has developed different strategies to escape NK-cell surveillance, preventing the expression of ligands for some activating receptors (ie, NKG2D, DNAM-1) 4-9 or selectively maintaining inhibitory receptors for HLA class I molecules engaged. The UL18 glycoprotein binds with high affinity to the LILRB1 inhibitory receptor expressed in different leukocytes 10 ; yet, formal experimental evidence for its function in immune evasion remains elusive. 11 In the same line, a leader signal peptide of the UL40 HCMV protein was shown to stabilize the surface expression of HLA-E, thus repressing NK-cell activation by engagement of the inhibitory CD94/NKG2A receptor. 12,13 On the other hand, the NK-cell subset bearing the CD94/NKG2C triggering molecule tends to expand in peripheral blood from HCMV ϩ persons 14 and on in vitro coculture of peripheral blood mononuclear cells (PBMCs) with HCMV-infected fibroblasts. 15 A CD94/NKG2C ϩ NK lymphocytosis was detected in a patient with a selective T-cell deficiency, coinciding with an acute HCMV infection and associated with a reduction of viremia. 16 Altogether, these results suggest that the CD94/NKG2C ϩ NK-cell subset may play an active role in the response to HCMV.Information on the nature of NK-cell receptor (NKR)-ligand interactions involved in the response against HCMV-infected cells is scarce, and most studies have been performed in infected fibroblasts, not fully representative of the different cell types susceptible to in vivo infection. Cells of the myeloid lineage are considered reservoirs for HCMV latency, and differentiation of myeloid progenitors to dendritic cells (DCs) may reactivate the virus. 17 Furthermore, monocyte-derived DCs (moDCs) appear susceptible to in vitro HCMV infection by endothelial cell (EC)-adapted viral strains. 18 Infection of moDCs has been reported to impair their maturation, inhibiting surface expression of major histocompatibility complex class I and II, costimulatory molecules, and chemokine receptors (ie, CCR1 and CCR5), thus interfering with the development of virus-specific T-cell responses. [19][20][21] Beyond their key role in antigen presentation, DCs may establish a cross-talk with NK cells that reciprocally regulates their Submitted August 9, 2010; accepted October 13, 2010. Prepublished online as Blood First Edition paper, October 28, 2010; DOI 10.118...

Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets

“…Even though these results do not rule out a contribution of activating KIR to the expansion of adaptive NK cells, they suggest the participation of DAP-12-independent pathway(s) in HCMV-adaptive NK cell differentiation. In this regard, NKp46 has been previously involved in the recognition of HCMV-infected dendritic cells and macrophages (42,43). It is conceivable that NKp46 engagement by HCMVinfected cells might provide an FcRg-dependent trigger for initial events in NK cell proliferation/differentiation.…”

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

“…Notably, the ligand on MCA-transformed cells undergoes immune editing by NKp46/NCR1 pressure (14), whereas the ligand on D122 cells described in this study apparently does not. Finally, we have recently shown that a ligand for NKp46/NCR1 is expressed by human and mouse b cells (27,28), and it was also demonstrated that upon human CMV infection of dendritic cells, an unknown ligand of NKp46/NCR1 is downregulated to prevent NK cell-mediated lysis of the infected dendritic cells (30)(31)(32)(33).…”

“…For example, human NKG2D recognizes eight different ligands (MICA, MICB, and ULBP1-6) (34), and NKp30 recognizes the pp65 protein of human CMV (35), BAT3 (36), B7-H6 (37), the HA of pox viruses (29), and another unknown ligand expressed by dendritic cells (33). It is possible that each NK activating receptor recognizes various ligands to enable the detection of a wide spectrum of tumors and pathogens via the usage of a limited number of receptors.…”

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

“…In vitro, NKG2C bright NK cells display a moderate response against HCMV-infected cells, although a recent study disclosed their possible role as Ab-dependent effectors (28,29), in close resemblance with FcεRg-chain-deficient NK cells (19).…”