NK cell cytotoxicity is controlled by numerous NK inhibitory and activating receptors. Most of the inhibitory receptors bind MHC class I proteins and are expressed in a variegated fashion. It was recently shown that TIGIT, a new protein expressed by T and NK cells binds to PVR and PVR-like receptors and inhibits T cell activity indirectly through the manipulation of DC activity. Here, we show that TIGIT is expressed by all human NK cells, that it binds PVR and PVRL2 but not PVRL3 and that it inhibits NK cytotoxicity directly through its ITIM. Finally, we show that TIGIT counter inhibits the NK-mediated killing of tumor cells and protects normal cells from NK-mediated cytoxicity thus providing an “alternative self” mechanism for MHC class I inhibition.

https://www.pnas.org/content/pnas/106/42/17858.full.pdf

The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity

Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.

/pdf/innate-or-adaptive-immunity-the-example-of-natural-killer-4ruyb8oaa3.pdf

Innate or Adaptive Immunity? The Example of Natural Killer Cells

Human CD56(bright) NK cells accumulate in the maternal decidua during pregnancy and are found in direct contact with fetal trophoblasts. Several mechanisms have been proposed to explain the inability of NK cells to kill the semiallogeneic fetal cells. However, the actual functions of decidual NK (dNK) cells during pregnancy are mostly unknown. Here we show that dNK cells, but not peripheral blood-derived NK subsets, regulate trophoblast invasion both in vitro and in vivo by production of the interleukin-8 and interferon-inducible protein-10 chemokines. Furthermore, dNK cells are potent secretors of an array of angiogenic factors and induce vascular growth in the decidua. Notably, such functions are regulated by specific interactions between dNK-activating and dNK-inhibitory receptors and their ligands, uniquely expressed at the fetal-maternal interface. The overall results support a 'peaceful' model for reproductive immunology, in which elements of innate immunity have been incorporated in a constructive manner to support reproductive tissue development.

Decidual NK cells regulate key developmental processes at the human fetal-maternal interface

Modulation of natural killer cell activity by viruses.

Most infectious agents enter the body at mucosal surfaces and therefore mucosal immune responses function as a first line of defence. Protective mucosal immune responses are most effectively induced by mucosal immunization through oral, nasal, rectal or vaginal routes, but the vast majority of vaccines in use today are administered by injection. As discussed in this Review, current research is providing new insights into the function of mucosal tissues and the interplay of innate and adaptive immune responses that results in immune protection at mucosal surfaces. These advances promise to accelerate the development and testing of new mucosal vaccines against many human diseases including HIV/AIDS.

/pdf/mucosal-vaccines-the-promise-and-the-challenge-1pfgw9qeyx.pdf

Mucosal vaccines: the promise and the challenge

Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined. NKp46 is thought to be the main activating receptor for human NK cells. Here we show that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein.

Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells

The aim of the present study was to examine a possible involvement of leukotrienes (LTs) in lipopolysaccharide (LPS)-induced body temperature (Tb) response. We examined the effect of MK-886, an inh...

Evidence supporting involvement of leukotrienes in LPS-induced hypothermia in mice

http://www.tau.ac.il/~ehudq/index_files/6-Qimron-Mucsoal%20vs%20systemic%20Vaccine%202004.pdf

Non-replicating mucosal and systemic vaccines: quantitative and qualitative differences in the Ag-specific CD8(+) T cell population in different tissues.

The relationship between hypothalamic prostaglandin E2 or leukotrienes and the body temperature response to lipopolysaccharide in different murine strains

Lada Paul

Papers

Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells

Evidence supporting involvement of leukotrienes in LPS-induced hypothermia in mice

Non-replicating mucosal and systemic vaccines: quantitative and qualitative differences in the Ag-specific CD8(+) T cell population in different tissues.

The relationship between hypothalamic prostaglandin E2 or leukotrienes and the body temperature response to lipopolysaccharide in different murine strains

Evidence for the involvement of eicosanoids in the regulation of normal body temperature