The HLA-G cycle provides for both NK tolerance and immunity at the maternal–fetal interface

Abstract

The interaction of noncytotoxic decidual natural killer cells (dNK) and extravillous trophoblasts (EVT) at the maternal–fetal interface was studied. Confocal microscopy revealed that many dNK interact with a single large EVT. Filamentous projections from EVT enriched in HLA-G were shown to contact dNK, and may represent the initial stage of synapse formation. As isolated, 2.5% of dNK contained surface HLA-G. However, surface HLA-G–negative dNK contained internalized HLA-G. Activation of dNK resulted in the disappearance of internalized HLA-G in parallel with restoration of cytotoxicity. Surface HLA-G was reacquired by incubation with EVT. This HLA-G cycle of trogocytosis, endocytosis, degradation, and finally reacquisition provides a transient and localized acquisition of new functional properties by dNK upon interaction with EVT. Interruption of the cycle by activation of dNK by cytokines and/or viral products serves to ensure the NK control of virus infection at the interface, and is illustrated here by the response of dNK to human cytomegalo virus (HCMV)-infected decidual stromal cells. Thus, the HLA-G cycle in dNK can provide both for NK tolerance and antiviral immunity.

Cytotoxic potential of decidual NK cells and CD8+ T cells awakened by infections

“…The role of dNK in clearance of virus infections, a main function of pNK, has been ignored until recently, Siewiera et al, 2013 demonstrated the ability of dNK to clear Human Cytomegalovirus (HCMV)-infected cells. Our lab has built upon this observation and highlighted the dual role of dNK, capable of mounting cytolytic responses during viral infections as well as both providing immune tolerance to the fetus and facilitating placental growth (Tilburgs et al, 2015b). …”

“…Despite the abundance of cytolytic granules, dNK are not able to kill Major Histocompatibility Antigen (MHC) Class I negative target cells (e. g. cell lines K652 or 721.221) efficiently as do pNK. The low cytotoxicity of dNK is due to an intrinsic block in the polarization of cytolytic granules to the immune synapse that can be overcome by incubating dNK with IL-15 (Kopcow et al, 2005; Tilburgs et al, 2015b). Thus dNK require additional activation by cytokines or activating NK receptor-ligand interactions to display their full cytotoxicity.…”

Expression of KIR2DS1 by decidual natural killer cells increases their ability to control placental HCMV infection

“…Our laboratory and others have shown that dNK have many differences in gene expression, cytokine secretion, and cytolytic capacity in comparison with pNK (2,(9)(10)(11)(12). Furthermore, dNK form immune synapses with EVT in which perforin is not localized to the synaptic region, a feature typical of a nonlytic synapse (13). During these immune synapses, dNK acquired HLA-G from the EVT through trogocytosis.…”

A distant trophoblast-specific enhancer controls HLA-G expression at the maternal–fetal interface

“…Several inhibitory receptors present on natural killer (NK) cells, the most abundant immune cell type at the maternal-fetal interface, and on myeloid cells, have been shown to bind to HLA-G (5-7). An HLA-G cycle between decidual NK cells and EVTs provides for both NK cell tolerance and antiviral immunity (8)(9)(10). Importantly, HLA-G is sufficient to inhibit NK cell cytotoxicity (11) and required to protect trophoblasts against NK cell-induced lysis (12).…”