Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives T<sub>H</sub>17 Cell Development during Hepatitis C Virus Infection

Wang, Jia M.; Shi, Lei; Cheng, Jun; Xiao, Ji; Ying, Ruo S.; Wu, Xiao Y.; Wang, Ke S.; Li, Guangyu; Moorman, Jonathan P.; Yao, Zhi Q.

doi:10.1128/jvi.03376-12

Cited by 38 publications

(46 citation statements)

References 45 publications

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“…These results are in agreement with our previous observations that another negative signaling molecule, T cell immunoglobulin and mucin domain protein 3 (Tim-3), is upregulated on NK cells to dampen their functions, with inhibited activation (CD69), proliferation (Ki69), degranulation (CD107a), and killing activity (granzyme B) following HCV infection (data not shown). This in turn interplays with monocytes and T cells (including Th17 and Foxp3 ϩ Tregs) in immune dysregulation that contribute to viral persistence (42)(43)(48)(49). This also supports the notion that HCV may utilize KLRG1-an intrinsic mercenary of cell feedback regulation-for the purpose of virus persistence and thus facilitate chronic infection.…”

Section: Discussionsupporting

confidence: 59%

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

Wang

Cheng

Shi

et al. 2013

J Virol

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In this study, we demonstrate that killer cell lectin-like receptor subfamily G member 1 (KLRG1), a transmembrane protein preferentially expressed on T cells, is highly expressed on CD56 ؉ NK cells, which are significantly reduced in their numbers and functions in the peripheral blood of patients with chronic hepatitis C virus (HCV) infection compared to subjects without infection. KLRG1 expression is also upregulated on healthy NK cells exposed to Huh-7 hepatocytes infected with HCV in vitro. Importantly, the expression levels of KLRG1 are inversely associated with the capacity of NK cells to proliferate and to produce gamma interferon (IFN-␥) but positively associated with apoptosis of NK cells in response to inflammatory cytokine stimulation. KLRG1؉ NK cells, including CD56 bright and CD56 dim subsets, exhibit impaired cell activation and IFN-␥ production but increased apoptosis compared to KLRG1؊ NK cells, particularly in HCV-infected individuals. Importantly, blockade of KLRG1 signaling significantly recovered the impaired IFN-␥ production by NK cells from HCV-infected subjects. Blockade of KLRG1 also enhanced the impaired phosphorylation of Akt (Ser473) in NK cells from HCV-infected subjects. Taken together, these results indicate that KLRG1 negatively regulates NK cell numbers and functions via the Akt pathway, thus providing a novel marker and therapeutic target for HCV infection.

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Section: Discussionsupporting

confidence: 59%

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

Wang

Cheng

Shi

et al. 2013

J Virol

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“…Elevated plasma IL-23 levels have been associated with chronic hepatitis C virus genotype 4 infection, 18 and monocytes from chronic HCV patients have exaggerated IL-23 production in vitro. 19 However, these studies do not assess response to therapy, and no data exist on IL-23 levels with HCV therapy, or the potential role of IL-23 as a mechanism of viral clearance. In this study, we indicate for the first time that IL-23 concentration differs with clinical outcome in HIV/HCVcoinfected subjects.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-23 Promotes Interferon-α Responsiveness in Hepatitis C Virus/HIV-Coinfected Patients

OdigieMadeline

OsinusiAnu

BarrettLisa

et al. 2014

AIDS Research and Human Retroviruses

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Patients coinfected with HIV and hepatitis C virus (HCV) have poor to modest rates of response with interferon-based therapies, which remain a backbone of the treatment in HIV/HCV-coinfected patients. The mechanisms responsible for poor responsiveness to interferon are not well described. In this study a targeted proteomic analysis of plasma from 42 patients infected with both HIV and HCV and undergoing therapy for HCV with peginterferon and ribavirin was performed. Higher baseline plasma levels of interleukin (IL)-23 were associated with sustained virologic response. Further investigation of how IL-23 facilitates interferon (IFN) responsiveness, as evidenced by a >2-fold increase in most interferon-stimulated genes (ISGs), revealed that IL-23 indirectly enhances IFN signaling in peripheral blood mononuclear cells and HCV continuous culture system by preventing the down-regulation of the IFNAR2 receptor after exposure to IFN-α. These findings suggest a unique role of the IL-23 pathway in enhancing host response to type I interferons, thereby facilitating eradication of HCV. Low levels of IL-23 present in plasma of nonresponders may reflect an impaired immune state that in the case of HIV/HCV-coinfected subjects could potentially lead to disruption of TH17 CD4(+) T cells. This study suggests a major role for HIV-associated immune dysregulation present in HIV-infected subjects that subsequently determines the overall responsiveness to exogenous interferon-α-based HCV therapy.

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“…Concordantly, expression is increased on monocytes from patients with HCV infection and is positively correlated with IL-17 levels in CD4 + T cells, thus promoting Th17 cell accumulation. However, blocking Tim-3 on monocytes restores the balance of IL-12, IL-23 and IL-17 signaling via the STAT3 pathway [50,51] .…”

Section: Tim-3 and Monocytes/macrophagesmentioning

confidence: 99%

Role of Tim-3 in hepatitis B virus infection: An overview

Liu

Gao

Liang

et al. 2016

WJG

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Hepatitis B virus (HBV) infection has received increasing public attention. hBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the abovementioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of hBV-related liver disease and suggest new therapeutic methods for intervention.

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Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives T_H17 Cell Development during Hepatitis C Virus Infection

Cited by 38 publications

References 45 publications

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

Interleukin-23 Promotes Interferon-α Responsiveness in Hepatitis C Virus/HIV-Coinfected Patients

Role of Tim-3 in hepatitis B virus infection: An overview

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Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives TH17 Cell Development during Hepatitis C Virus Infection

Cited by 38 publications

References 45 publications

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

KLRG1 Negatively Regulates Natural Killer Cell Functions through the Akt Pathway in Individuals with Chronic Hepatitis C Virus Infection

Interleukin-23 Promotes Interferon-α Responsiveness in Hepatitis C Virus/HIV-Coinfected Patients

Role of Tim-3 in hepatitis B virus infection: An overview

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Differential Regulation of Interleukin-12 (IL-12)/IL-23 by Tim-3 Drives T_H17 Cell Development during Hepatitis C Virus Infection