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

The integrated processing of signals transduced by activating and inhibitory cell surface receptors regulates NK cell effector functions. Here, I review the structure, function, and ligand specificity of the receptors responsible for NK cell recognition.

Nk cell recognition

Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.

/pdf/molecular-mechanisms-of-t-cell-co-stimulation-and-co-5cdjz3spxg.pdf

Molecular mechanisms of T cell co-stimulation and co-inhibition

The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.

/pdf/the-extracellular-matrix-a-dynamic-niche-in-cancer-21xcbo41km.pdf

The extracellular matrix: A dynamic niche in cancer progression

Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.

LAIR-1, a Novel Inhibitory Receptor Expressed on Human Mononuclear Leukocytes

Collagens are the most abundant proteins in the human body, important in maintenance of tissue structure and hemostasis. Here we report that collagens are high affinity ligands for the broadly expressed inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1). The interaction is dependent on the conserved Gly-Pro-Hyp collagen repeats. Antibody cross-linking of LAIR-1 is known to inhibit immune cell function in vitro. We now show that collagens are functional ligands for LAIR-1 and directly inhibit immune cell activation in vitro. Thus far, all documented ligands for immune inhibitory receptors are membrane molecules, implying a regulatory role in cell–cell interaction. Our data reveal a novel mechanism of peripheral immune regulation by inhibitory immune receptors binding to extracellular matrix collagens.

/pdf/collagens-are-functional-high-affinity-ligands-for-the-1za7ammuul.pdf

Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1

The immune system protects the body from invaders such as viruses and bacteria. Immune cells must be activated in the correct context to function properly. It is critical that the receptors, costimulatory molecules, and cytokines that orchestrate this activation are carefully regulated to prevent uncontrolled inflammation and autoimmunity. Inhibitory receptors play an important role in regulation of immune cell function, usually upon interaction with ligands present on other cells. In contrast, the function of the inhibitory leukocyte-associated Ig-like receptor (LAIR)-1 can be regulated by extracellular matrix collagens. LAIR-1 is expressed on most cells of the immune system, and its function has been studied on multiple cell types. This review summarizes current literature about LAIR-1, a receptor that potentially is able to regulate multiple steps of an immune response.

/pdf/the-inhibitory-collagen-receptor-lair-1-cd305-1r6i4jnp8g.pdf

The inhibitory collagen receptor LAIR-1 (CD305).

https://dspace.library.uu.nl/bitstream/handle/1874/32301/LM%20the%20inhibitory%20CD200R.pdf;sequence=1

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes.

Leukocyte associated Ig-like receptor-1 (LAIR-1) is a surface molecule expressed on human mononuclear leukocytes that functions as an inhibitory receptor on human NK cells. In addition to NK cells, LAIR-1 is expressed on T cells, B cells, macrophages, and dendritic cells. Most cells express two biochemically distinct forms of LAIR-1, which we now show are likely alternative splice variants of the same gene. Cross-linking of LAIR-1 on human T cell clones results in inhibition of cytotoxicity only in T cell clones that lack CD28 and are able to spontaneously lyse certain targets in vitro. Moreover, the cytolytic activity of freshly isolated T cells, which is thought to be mainly due to “effector” T cells, can be inhibited by anti-LAIR-1 mAb. Thus, LAIR-1 functions as an inhibitory receptor not only on NK cells, but also on human T cells. This indicates that LAIR-1 provides a mechanism of regulation of effector T cells and may play a role in the inhibition of unwanted bystander responses mediated by Ag-specific T cells.

Linde Meyaard

Papers

LAIR-1, a Novel Inhibitory Receptor Expressed on Human Mononuclear Leukocytes

Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1

The inhibitory collagen receptor LAIR-1 (CD305).

The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes.

Leukocyte-associated Ig-like receptor-1 functions as an inhibitory receptor on cytotoxic T cells.