Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

Rodrigue-Gervais, Ian Gaël; Rigsby, Hawley; Jouan, Loubna; Sauvé, Dominike; Sékaly, Rafick‐Pierre; Willems, Bernard; Lamarre, Daniel

doi:10.4049/jimmunol.0902522

Cited by 54 publications

(47 citation statements)

References 48 publications

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“…Dysfunctional DCs are involved in the exhaustion of CD8 ? T cells, confirming that DCs play an important role in linking the innate immune system to the adaptive immune system [82] Monocyte-derived DCs generated from hepatitis C patients have been shown to have an impaired ability to stimulate allogeneic CD4 T cells [83,84], with a decrease in the functional impairment of DCs when HCV was eradicated from patients, thereby providing evidence for HCV-induced DC disability [83]. NK cells from HCV-infected patients are able to downregulate DC functions in the presence of hepatocytes by secreting the suppressive cytokines IL-10 and transforming growth factor beta-1 [85].…”

Section: Dcs In Chronic Hcv Infectionmentioning

confidence: 68%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Section: Dcs In Chronic Hcv Infectionmentioning

confidence: 68%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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“…In contrast to acute infection, optimal polyfunctional memory T cell responses are lost in chronic infections and cancer, both in humans and mice (5,8,9). These cells have been characterized as "exhausted" (8,10) and factors promoting the development of T cell exhaustion include persistent and high levels of antigen stimulation (11,12), DC inhibition (3), and upregulation of inhibitory receptors, such as PD-1, on T cells (13)(14)(15)(16)(17). While recent work has highlighted a role for PD-1 and other inhibitory receptors in T cell exhaustion, blockade of inhibitory receptor signaling in HIV-specific T cells had only a moderate effect in reversing the exhaustion phenotype and increasing T cell polyfunctionality (14,15), thus indicating that additional molecular mechanisms are involved in the inhibition of T cell polyfunctionality.…”

Section: Introductionmentioning

confidence: 99%

Sprouty-2 regulates HIV-specific T cell polyfunctionality

et al. 2013

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The ability of individual T cells to perform multiple effector functions is crucial for protective immunity against viruses and cancer. This polyfunctionality is frequently lost during chronic infections; however, the molecular mechanisms driving T cell polyfunctionality are poorly understood. We found that human T cells stimulated by a high concentration of antigen lacked polyfunctionality and expressed a transcription profile similar to that of exhausted T cells. One specific pathway implicated by the transcription profile in control of T cell polyfunctionality was the MAPK/ERK pathway. This pathway was altered in response to different antigen concentrations, and polyfunctionality correlated with upregulation of phosphorylated ERK. T cells that were stimulated with a high concentration of antigen upregulated sprouty-2 (SPRY2), a negative regulator of the MAPK/ERK pathway. The clinical relevance of SPRY2 was confirmed by examining SPRY2 expression in HIV-specific T cells, where high levels of SPRY2 were seen in HIV-specific T cells and inhibition of SPRY2 expression enhanced the HIV-specific polyfunctional response independently of the PD-1 pathway. Our findings indicate that increased SPRY2 expression during chronic viral infection reduces T cell polyfunctionality and identify SPRY2 as a potential target for immunotherapy.

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“…Therefore, the enhanced infection of DCs, followed by reduced T cell stimulatory capacity, is probably one of the mechanisms by which chronic pathogens initiate immunosuppression within the host (79,80). More interestingly, independent of preferential DC infection by chronic pathogens, it has been reported that the functional impairment of DCs is associated with the exhaustion of T cell function and progression of disease during HIV, HBV, HCV, and LCMV infections (81)(82)(83)(84)(85)(86). However, the molecular mechanisms underlying impaired T cell function mediated by DCs during chronic pathogen infection have to be fully elucidated.…”

Section: Extrinsic Factors Regulating T Cell Immunity In a Chronic Anmentioning

confidence: 99%