Hepatitis C Virus–Induced Secretion of Inflammatory Chemokines Preferentially Recruits NKG2A<sup>+</sup>CD8<sup>+</sup>T Cells

Nattermann, Jacob; Sherzada, R.; Iwan, Agathe; Bogen, Dominik; Niederle, Ina Maria; Schulte, Daniela; Mertens, Eva; Nischalke, Hans Dieter; Krämer, Benjamin; Sauerbruch, Tilman; Leifeld, Ludger; Spengler, Ulrich

doi:10.1086/589309

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…The three receptors share chemokine ligands: CCR5 interacts with CCL3, CCL4, CCL5 and CCL8; CCR2 with CCL2, CCL13, CCL7 and CCL8; and CCR1 with CCL3, CCL5, CCL7, CCL23 and CCL14-16 [3,89] . All of these chemokines have been detected in the liver [51,56,[90][91][92] . CCR1, CCR2 and CCR5 expression is characteristic of memory T cells and CCR5 is expressed on Th1 cells [89,93] , with particularly high frequencies detected in the human liver [51,55,90] .…”

Section: Ccr5 and Ccr1/ccl5 And Liver Inflammationmentioning

confidence: 99%

The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

Shetty

Adams³

2010

Dig Dis

147

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Chemokines direct leukocyte trafficking and positioning within tissues, thus playing critical roles in regulating immune responses and inflammation. The chemokine system is complex, involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low-flow environment through which leukocytes are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum, fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure; at the other end, diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is characterized by a T lymphocyte-rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells, and more recently Th17 and Th9 cells, which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate disease pathogenesis and open up new therapeutic approaches to modulate recruitment in favor of resolution rather than injury.

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Section: Ccr5 and Ccr1/ccl5 And Liver Inflammationmentioning

confidence: 99%

The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

Shetty

Adams³

2010

Dig Dis

147

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“…The receptors share chemokine ligands; CCR5 interacts with CCL3, CCL4, CCL5 and CCL8; and CCR2 interacts with CCL2, CCL13, CCL7 and CCL8 all of which have been detected in the liver30,80. CCR5 ligands are strongly expressed on portal endothelium81 and in murine models of graft versus host disease CCR5 and CCL3 support effector cell recruitment to portal tracts64.…”

Section: Adaptive Immune Response and T Cell Recruitment In Hcvmentioning

confidence: 99%

“…These T cells are attracted to the liver in response to CCR5 ligands induced by HCV E2 antigen. However engagement of the NKG2A receptor results in their inactivation demonstrating another mechanism by which HCV can manipulate chemokine networks to subvert effective immune responses80. The consequences of HCV on T cells can be unpredictable; for example although HCV-E2 binding to CD81 on CD8 T cells increases CCL5 secretion this causes autocrine desensitization of CCR5 and a loss of migratory capacity82.…”

Section: Adaptive Immune Response and T Cell Recruitment In Hcvmentioning

confidence: 99%

Chemokines in the immunopathogenesis of hepatitis C infection

2008

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Hepatitis C Virus (HCV) ImmunopathologyHCV is a hepatotropic virus consisting of a polyprotein processed into structural proteins (core and envelope proteins 1 and 2), nonstructural proteins (NS2 to NS5), and a protein of unknown function (p7). 1,2 The viral polymerase lacks proof-reading capability, and this results in the generation of sequence diversity and quasispecies that contribute to evasion of the host immune response and chronic infection. [2][3][4] Although hepatocytes are the primary target of HCV, the virus can interact with monocyte, lymphocyte, and endothelial cells. 5,6 The recent description of in vitro models of HCV replication is elucidating HCV biology, 7 but the lack of small-animal models hinders studies of disease course and outcome. 3 The liver is a unique immunological environment with a dual blood supply and distinct rheological requirements for leukocyte recruitment. Although hepatic immune tolerance prevents exuberant responses to food antigen, 8 the liver can generate strong immune responses to infections, including hepatitis A and E viruses. 9 In general, a vigorous intrahepatic immune response requires activation of T cells by activated dendritic cells (DCs) within secondary lymphoid tissues, whereas activation within the liver by hepatocytes or endothelial cells results in tolerance. 10 This allows the liver to tolerate food antigens captured by endothelial cells and self-antigens on hepatocytes while responding appropriately to infections that cause inflammation and activation of DCs. The ability of HCV to infect hepatocytes without causing marked inflammatory damage may prevent the activation of a full immune response. 2,11 Whether HCV infection is acute and self-limiting or persistent is determined early. 3,4 The first line of defense is provided by infected hepatocytes that secrete interferon (IFN) and down-regulate RNA translation in response to infection before innate immune cells, including macrophages, DCs, natural killer (NK) cells, and natural killer T (NKT) cells, are activated to amplify secretion of type I IFNs and IFN-response genes. Activation of pattern recognition receptors, particularly Toll-like receptors, trig-

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“…However, these relationships appear to be more complex. We recently showed that CCR5 (+) lymphocytes are characterized by a high expression of the inhibitory NK cell receptor NKG2A [21]. Therefore, these cells are very sensitive to NKG2A-mediated inhibition of cytotoxic function.…”

Section: Hcv and Ccr5mentioning

confidence: 99%

The role of CCR5 in HCV infection

Coenen

Nattermann

2010

Eur J Med Res

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Efficient recruitment and activation of immuno-competent cells is crucial for an effective immune response to hepatitis C virus (HCV) infection. Chemokines and chemokine receptors have been shown to be critically involved in these processes.The CCR5 chemokine receptor is expressed on several cells of the immune system and has been suggested to influence the susceptibility to HCV infection as well as natural course and progression of hepatitis C. However, these reports are still controversial.This review will summarize and discuss the available data regarding the potential role of CCR5 and its ligands in hepatitis C.

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Hepatitis C Virus–Induced Secretion of Inflammatory Chemokines Preferentially Recruits NKG2A⁺CD8⁺T Cells

Cited by 7 publications

References 15 publications

The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

Chemokines in the immunopathogenesis of hepatitis C infection

The role of CCR5 in HCV infection

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Hepatitis C Virus–Induced Secretion of Inflammatory Chemokines Preferentially Recruits NKG2A+CD8+T Cells

Cited by 7 publications

References 15 publications

The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

Chemokines in the immunopathogenesis of hepatitis C infection

The role of CCR5 in HCV infection

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Product

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Hepatitis C Virus–Induced Secretion of Inflammatory Chemokines Preferentially Recruits NKG2A⁺CD8⁺T Cells