LIGHT Is Constitutively Expressed on T and NK Cells in the Human Gut and Can Be Induced by CD2-Mediated Signaling

Cohavy, Offer; Zhou, Jaclyn S; Ware, Carl F.; Targan, Stephan R.

doi:10.4049/jimmunol.174.2.646

Cited by 65 publications

(56 citation statements)

References 48 publications

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“…27 Studies in animal models suggest that LIGHT signaling pathways may be crucial for the development of various autoimmune disorders, at least in part because of their effects on T cells (eg, increased production of interferon-␥) and T-cell homing into inflamed tissues. 28,29 In the present study, we extend these findings, showing profound effects of LIGHT on THP-1 macrophages that lead to enhanced lipid accumulation and increased levels of prothrombotic mediators. Importantly, a similar LIGHT-induced pattern was also seen in human monocyte-derived macrophages.…”

Section: Discussionsupporting

confidence: 65%

Enhanced Plasma Levels of LIGHT in Unstable Angina

et al. 2005

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Background-Numerous studies have demonstrated the ability of oxidized LDL [(ox)LDL] to promote an inflammatory response in macrophages. Several inflammatory mediators have been reported to increase after oxLDL stimulation of such cells, but their relative importance is still unknown. In the present study, we used microarrays to identify genes in THP-1 macrophages that were upregulated by oxLDL. Methods and Results-Our main findings were as follows. In a microarray screening experiment, we identified LIGHT, a ligand in the tumor necrosis factor superfamily, as one of the genes that were markedly upregulated in oxLDL-stimulated THP-1 macrophages. We showed significantly raised plasma levels of LIGHT in patients with stable angina (nϭ40) and particularly in those with unstable angina (nϭ40) compared with healthy controls (nϭ20), which underscores the clinical relevance of the in vitro finding. We also showed that LIGHT enhanced lipid accumulation in oxLDL-stimulated THP-1 macrophages, possibly through upregulation of class A scavenger receptor (SR-A). This increased lipid accumulation was accompanied by enhanced expression of tissue factor and plasminogen activator inhibitor-1, as well as enhanced thrombin formation, transforming macrophages into a prothrombotic phenotype. The LIGHT-mediated increase in SR-A, tissue factor, and plasminogen activator inhibitor-1 was also seen in human monocyte-derived macrophages. Finally, the LIGHT-mediated enhancement of SR-A and TF expression appears to involve nuclear factor-B activation. Conclusions-These findings suggest that LIGHT could serve as a molecular link between lipid metabolism, inflammation, and thrombus formation, which are all features of atherosclerotic plaques.

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Section: Discussionsupporting

confidence: 65%

Enhanced Plasma Levels of LIGHT in Unstable Angina

et al. 2005

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“…Human NK cells expressing TNFSF14 have previously been observed in the gut, where its expression is constitutive (38). Our results demonstrate its very rapid induction on peripheral blood-derived NK cells in response to a variety of stimuli.…”

Section: Discussionsupporting

confidence: 57%

Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

Holmes

Wilson

Black

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor-and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.natural killer cells | NK-DC interactions | TNFSF14 | NK-cell licensing | tumor immunity N atural killer (NK) cells play an important role in protecting the host against viral infection and cancer. As well as having potent cytotoxic activity, NK cells are endowed with immunoregulatory activity (1, 2). For example, NK cell activation induces the production of chemokines, such as macrophage inflammatory protein-1α (MIP-1α) and IL-8, and proinflammatory cytokines, such as IFN-γ, GM-CSF, and TNF-α. These molecules regulate the recruitment and activity of numerous immune cell types (1, 2). Importantly, NK cells can promote development of T-cell responses via NK-dendritic cell (DC) interactions that favor both DC maturation and NK-cell activation (3-5), with NK cell-derived IFN-γ skewing T-cell differentiation toward the Th1 phenotype (6, 7).Cytotoxic activity and cytokine production are coupled to signaling pathways downstream of a repertoire of activating and inhibitory receptors; signals from activating receptors (including NKG2D, DNAM-1, and 2B4, as well as the natural cytotoxicity receptors NKp30, NKp44, and NKp46) compete with signals from inhibitory receptors such as the killer cell immunoglobulinlike receptors (KIRs) and CD94/NKG2A heterodimers to regulate activation. In addition, NK cells express CD16, the lowaffinity receptor for IgG, conferring antibody-dependent cellular cytot...

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“…It would seem logical that NK cells would contribute to inflammation within the intestinal tract during CLPinduced injury. The intestinal wall contains large numbers of NK cells in subepithelial regions as well as in the lamina propria (16). Several studies have shown that NK cells contribute to intestinal inflammation during enteric infections and inflammatory bowel disease (17)(18).…”

Section: Discussionmentioning

confidence: 99%

NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis

Etogo

Nunez

Chen

et al. 2008

The Journal of Immunology

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Evidence suggests that NK and NKT cells contribute to inflammation and mortality during septic shock caused by cecal ligation and puncture (CLP). However, the specific contributions of these cell types to the pathogenesis of CLP-induced septic shock have not been fully defined. The goal of the present study was to determine the mechanisms by which NK and NKT cells mediate the host response to CLP. Control, NK cell-deficient, and NKT cell-deficient mice underwent CLP. Survival, cytokine production, and bacterial clearance were measured. NK cell trafficking and interaction with myeloid cells was also studied. Results show that mice treated with anti-asialoGM1 (NK cell deficient) or anti-NK1.1 (NK/NKT cell deficient) show less systemic inflammation and have improved survival compared with IgG-treated controls. CD1 knockout mice (NKT cell deficient) did not demonstrate decreased cytokine production or improved survival compared with wild type mice. Trafficking studies show migration of NK cells from blood and spleen into the inflamed peritoneal cavity where they appear to facilitate the activation of peritoneal macrophages (F4-80+GR-1−) and F4-80+Gr-1+ myeloid cells. These findings indicate that NK but not CD1-restricted NKT cells contribute to acute CLP-induced inflammation. NK cells appear to mediate their proinflammatory functions during septic shock, in part, by migration into the peritoneal cavity and amplification of the proinflammatory activities of specific myeloid cell populations. These findings provide new insights into the mechanisms used by NK cells to facilitate acute inflammation during septic shock.

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LIGHT Is Constitutively Expressed on T and NK Cells in the Human Gut and Can Be Induced by CD2-Mediated Signaling

Cited by 65 publications

References 48 publications

Enhanced Plasma Levels of LIGHT in Unstable Angina

Enhanced Plasma Levels of LIGHT in Unstable Angina

Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT

NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis

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