Human Cytomegalovirus-Specific CD4
            <sup>+</sup>
            -T-Cell Cytokine Response Induces Fractalkine in Endothelial Cells

Bolovan-Fritts, Cynthia; Trout, Rodney; Spector, Stephen A.

doi:10.1128/jvi.78.23.13173-13181.2004

Cited by 35 publications

(52 citation statements)

References 42 publications

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“…11,16,39 In our observations, up-regulated cell adhesion markers (ICAM-1, VCAM) together with cell-associated fractalkine indicate a contributing role for cell adhesion in the observed endothelial damage process. 33, 37 We also observed that NK and Figure 7. CMV-seropositive donor PBMCs exposed to CMV antigen results in endothelial damage in cocultures that is mediated predominantly by the fractalkine-CX3CR1 interaction.…”

Section: Discussionmentioning

confidence: 51%

“…33,37 In this report, we show that the fractalkine-CX 3 CR1 interaction plays an important role in mediating this endothelial damage together through recruitment of NK cells and monocyte-macrophages. The key role of fractalkine is emphasized by our blocking data, whereby the ability of specific antibody to CX 3 CR1 greatly reduced CX 3 CR1 ϩ -bearing cell chemoattraction and provided the greatest protection against endothelial cell damage.…”

Section: Discussionmentioning

confidence: 99%

Section: Endothelial Cell Damage Is Associated With Fractalkine Inducmentioning

confidence: 94%

“…33 In these studies, CD4ϩ T cells from CMV seronegative donors consistently failed to induce fractalkine in endothelial cells. 33 We had also shown that endothelial damage and loss follow induction of fractalkine in the presence of PBMCs from CMV-seropositive donors stimulated with CMV antigen. 37 Increased cell migration together with up-regulation of cell adhesion markers indicated that this damage occurred through a chemokinemediated process.…”

mentioning

confidence: 94%

“…We have reported that the host CD4 ϩ T-cell response to CMV antigen can produce IFN␥ and TNF␣ at levels sufficient to drive induction of fractalkine, a key marker of inflammation in endothelial cells. 10,27,33 In many seropositive persons, a relatively high percentage of the host T-cell response is invested in recognition of CMV antigens, emphasizing the potential of the host immune system to respond aggressively to CMV and contribute to a process of vascular inflammation leading to endothelial damage. [34][35][36] We have also observed a major pathogenic effect whereby endothelial cell damage and loss follow the induction of fractalkine and upregulation of cell adhesion markers in the presence of peripheral blood mononuclear cells (PBMCs) from donors with relatively higher frequencies of CMV-specific T cells.…”

mentioning

confidence: 99%

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Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Bolovan-Fritts

Spector

2008

Blood

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Human cytomegalovirus (CMV) infection has been linked to inflammatory diseases, including vascular disease and chronic transplant rejection, that involve vascular endothelial damage. We have previously shown that the host CD4(+) T-cell response to CMV antigen can produce IFNgamma and TNFalpha at levels sufficient to drive induction of fractalkine, a key marker of inflammation in endothelial cells. We have also observed a major pathogenic effect in which endothelial cell damage and loss follow the induction of fractalkine and up-regulation of cell adhesion markers in the presence of peripheral blood mononuclear cells (PBMCs) from donors with a high CMV-specific T-cell frequency. In this report, we show that the fractalkine-CX(3)CR1 interaction resulting in recruitment of natural killer (NK) cells and monocyte-macrophages plays an important role in mediating this endothelial damage. Supportive evidence for frac-talkine's key role is shown by the ability of specific antibody to CX(3)CR1 to reduce significantly CX(3)CR1(+)-bearing cell chemoattraction and to protect against endothelial damage. These findings support CMV as a member of a class of persistent pathogens in which a high T-cell response and chemokine-mediated effects are a risk factor for development of chronic inflammation and endothelial cell injury.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Endothelial Cell Damage Is Associated With Fractalkine Inducmentioning

confidence: 94%

mentioning

confidence: 94%

mentioning

confidence: 99%

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Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Bolovan-Fritts

Spector

2008

Blood

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Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells

et al. 2015

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CD8+ T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8 IntroductionUpon viral infection the immune system engages lymphocytes such as NK cells, CD4 + and CD8 + T cells to eliminate the virus. CD4+ and CD8 + T cells recognize viral peptides presented by MHC class II (MHC-II) and MHC class I (MHC-I) molecules respectively. CD8 + T cells specific for the infecting pathogen first undergo massive expansion before they differentiate into cytotoxic cells capable of producing high levels of effector molecules such as IL-2, IFN-γ, TNF-α, perforin and granzyme B [1, 2]. Naïve CD4 + T cells alsoCorrespondence: Dr. Klaas P. J. M. van Gisbergen e-mail: k.vangisbergen@sanquin.nl expand and develop an effector (Th1) phenotype capable of secreting copious amounts of IFN-γ, IL-2 and TNF-α to assist CD8 + T-cell and B-cell responses [3]. To avoid T-cell detection and lysis of the infected cells, viruses of the Herpesviridae family including human cytomegalovirus (HCMV) have evolved mechanisms to downregulate MHC-I molecules on infected cells [4,5]. In turn, NK cells can detect downregulation of MHC expression and produce inflammatory cytokines such as IFN-γ, TNF-α, and cytotoxic granules containing effector molecules, such as perforin and the serine protease granzyme B, to eliminate infected cells [6,7]. HCMV is a member of the Herpesviridae family of doublestranded DNA viruses and has coevolved with humans for millions of years [8]. HCMV has a broad tropism for a wide range of tissues including endothelium, fibroblasts, smooth muscle, and C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2434 Felipe A. Vieira Braga et al. Eur. J. Immunol. 2015. 45: 2433-2445 hematopoietic cells. HCMV is a prevalent human pathogen, with 40-70% of the western population being seropositive for HCMV [9]. HCMV induces persistent infection, which can be divided into acute and latent phases, and which are respectively characterized by active replication and quiescence of the virus [10]. The majority of HCMV-infected individuals do not develop any symptoms, but immunocompromised individuals, such as transplant recipients and HIV + patients, are a risk group for HCMV infection and can present with symptoms such as vascular complications [8].In order to follow T-cell responses in humans, we and others have made extensive use of instances of primary HCMV infection of transplant patients, which occurs when an HCMV − recipient receives an organ transplant from an HCMV + donor. Using this system, the data show that the initial early T-cell response against HCMV peaks on average 7 days after the first detection of circulating CMV-DNA. The T-cell response is initially dominated by CD4 + T cells that have a T-helper 1 type cytokine signature, with high production of the cytokines IFN-γ and TNF-α, but not of the classical T-helper 2 cytokine . A few days after the initial CD4 + T-cell response, HCMV-specific CD8 + T cells with high cytotoxic potential can be detected in blood. Remarkably, after th...

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Cx3cl1 (Fractalkine): A Signpost for Biliary Inflammation in Primary Biliary Cirrhosis

et al. 2010

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Improvements in the treatment of primary biliary cirrhosis (PBC) may depend upon dissection of mechanisms that determine recruitment of mononuclear cells to intralobular bile ducts, including the role of the chemokine-adhesion molecule CX3CL1 (fractalkine). We submit that there are unique interactions between intrahepatic biliary epithelial cells (BECs), endothelial cells (ECs), liver sinusoidal endothelial cells (LSECs), and liver-infiltrating mononuclear cells (LMCs), and that such interactions will in part dictate the biliary-specific inflammatory response. To address this, we studied fresh explanted livers from pretransplantation patients with PBC and with inflammatory liver disease due to viral infection (disease controls) and biopsy material from patients with a discrete liver tumor (normal controls). Using this clinical material, we isolated and stimulated BECs, ECs, LSECs, and LMCs with a panel of Toll-like receptor ligands. We also studied the interactions of these cell populations with LMCs with respect to adhesion capability and production of tumor necrosis factor ␣ (TNF-␣). Finally, we used fresh biopsy samples to evaluate mononuclear cells around intrahepatic biliary ductules using monoclonal antibodies specific to CD68 or CD154, markers for monocytes/macrophages, and activated T cells, respectively. Conclusion: There are common properties of ECs, LSECs, and BECs, whether derived from PBC or viral hepatitis, but there are also significant differences, particularly in the potential in PBC for LMCs to adhere to ECs and BECs and to produce TNF-␣; such properties were associated with augmented CX3CL1 production by BEC from PBC liver. The processes defined herein suggest potential novel biotherapies for biliary specific inflammation. (HEPATOLOGY 2010;51:567-575.) P revious work in our laboratory on inflammatory chemotaxis in primary biliary cirrhosis (PBC) has demonstrated participation of various chemokine ligands, 1 and studies in other laboratories have implicated the chemokine CX3CL1 (fractalkine) in inflammatory liver disease. 2,3 We therefore set out to examine the contribution of CX3CL1 4-9 to the bile duct destruction of PBC. Our previous findings in PBC indicated that CX3CL1 is elevated in serum concurrent with increased expression of the CX3CR1 receptor in liver-infiltrating mononuclear cells (LMCs), 10 leading us to posit that CX3CL1 could indeed be critical for the generation and persistence of the portal lymphocytic infiltration in PBC. We have herein taken advantage of our ability to isolate pure populations of multiple intrahepatic cell types, including endothelial cells (ECs), liver sinusoidal endothelial cells (LSECs), and biliary epithelial cells (BECs) to directly study the interaction of CX3CL1-producing cells with LMCs. We should note that several nonprofessional immunocompetent cells produce chemokines in response to ligands for Toll-like receptors (TLRs).

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Human Cytomegalovirus-Specific CD4 ⁺ -T-Cell Cytokine Response Induces Fractalkine in Endothelial Cells

Cited by 35 publications

References 42 publications

Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells

Cx3cl1 (Fractalkine): A Signpost for Biliary Inflammation in Primary Biliary Cirrhosis

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Human Cytomegalovirus-Specific CD4 + -T-Cell Cytokine Response Induces Fractalkine in Endothelial Cells

Cited by 35 publications

References 42 publications

Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction

Molecular characterization of HCMV‐specific immune responses: Parallels between CD8+ T cells, CD4+ T cells, and NK cells

Cx3cl1 (Fractalkine): A Signpost for Biliary Inflammation in Primary Biliary Cirrhosis

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Product

Resources

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Human Cytomegalovirus-Specific CD4 ⁺ -T-Cell Cytokine Response Induces Fractalkine in Endothelial Cells

Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells