Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection

Wherry, E. John; Ha, Sang Jun; Kaech, Susan M.; Haining, W. Nicholas; Sarkar, Surojit; Kalia, Vandana; Subramaniam, Shruti; Blattman, Joseph N.; Barber, Daniel L.; Ahmed, Rafi

doi:10.1016/j.immuni.2007.11.006

Cited by 1,382 publications

(182 citation statements)

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“…and 8 ? T-cell function [42][43][44], suggesting the PD-L1/PD-1 axis plays an important role in mediating T-cell exhaustion during chronic infection. Most human cancer tissues express variable levels of PD-L1 protein (reviewed in [8]).…”

Section: T-bet and Eomes Drive T-cell-mediated Adaptive Anti-tumor Immentioning

confidence: 99%

T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract

Chen

Liu

et al. 2011

Immunol Res

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Tumorigenesis can induce adaptive T-cell-mediated immune responses against malignant cells. Such cellular immune responses are actively suppressed by cancer cells via mechanisms of immune tolerance. We studied T-cell responses against tumor growth by examining tumor-infiltrating lymphocytes (TILs) in upper gastrointestinal (GI) cancers. The number of T-bet(+) TILs correlates with better survival of esophageal cancer patients. Using well-defined mouse models, we have further shown that T-bet and Eomes are both required for the adaptive anti-tumor immunity by regulating T-cell trafficking into the tumor tissue and their effector functions inside the tumor microenvironment. In order to gain further insight into the tumor immune microenvironment in the upper GI cancer, we have also studied expression levels of co-inhibitory molecules such as B7-H1/PD-L1 and B7-H4 in tissue specimens of esophageal and gastric cancers. These inhibitory B7 molecules were expressed at high but variable levels by cancer cells. The overexpression of these molecules correlates with poor clinicopathological parameters and shorter patient survival time. The number of CD3(+) and CD8(+) TILs correlates inversely with expression levels of B7-H4 in samples from esophageal cancer, supporting a role of active immune suppression by inhibitory B7 molecules in the tumor microenvironment. In addition, TILs show functional exhaustion and express high levels of PD-1 and Tim-3. We propose that metabolic competition mediated by phosphatidylinositol 3-kinases (PI3Ks) characterizes the immune suppression within cancer tissues. Future tumor vaccine design should combine blockade of B7 inhibitory molecules and enhancement of T-bet and Eomes levels within the tumor microenvironment.

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Section: T-bet and Eomes Drive T-cell-mediated Adaptive Anti-tumor Immentioning

confidence: 99%

T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract

Chen

Liu

et al. 2011

Immunol Res

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“…CD107a, a lysosome-associated membrane glycoprotein, is expressed on the cell surface during the release of cytotoxic granule contents (Betts et al, 2003;Alter et al, 2004). In chronic virus infections, CD8 + T cells suffer from a progressive loss of function in a mechanism termed T cell exhaustion (Wherry et al, 2007;Ha et al, 2008;Wirth et al, 2010;Wherry, 2011). These exhausted CD8 + T cells express high levels of programmed death 1 (PD-1) (Virgin et al, 2009), a CD28 family costimulatory/ coinhibitory molecule that promotes apoptosis in antigenspecific T cells while reduces regulatory T cell apoptosis (Francisco et al, 2010;Fife and Pauken, 2011), and T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) (Jones et al, 2008;Golden-Mason et al, 2009), a negative regulator of adaptive T cell responses (Anderson, 2012;Moorman et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Regulation of HBV-specific CD8+ T cell-mediated inflammation is diversified in different clinical presentations of HBV infection

et al. 2015

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Chronic HBV infection is the leading cause of liver cirrhosis and hepatic cancer, but the individual responses toward HBV infection are highly variable, ranging from asymptomatic to chronic active hepatitis B inflammation. In this study, we hypothesized that the different individual responses to HBV infection was associated with differences in HBV-specific CD8(+) T cell-mediated inflammation and cytotoxicity. Blood samples were collected from subjects with asymptomatic HBV-infection, subjects undergoing active chronic HBV flares (active CHB), and subjects with HBV-infected hepatocellular carcinoma (HBV-HCC). By tetramer staining, we found that all three groups had similar frequencies of HBVspecific CD8(+) T cells. However, after HBV peptide stimulation, the HBV-specific CD8(+) T cells in asymptomatic subjects had significantly stronger interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and CD107a expression than those in active CHB and HBV-HCC patients. Examination of surface marker expression revealed that the PD-1(-)Tim-3(-) double-negative cell population was the main contributor to HBV-specific inflammation. In active CHB patients and HBV-HCC patients, however, the frequencies of activated PD-1(-)Tim-3(-) cells were significantly reduced. Moreover, the serum HBV DNA titer was not correlated with the frequencies of HBV-specific CD8(+) T cells but was inversely correlated with the frequencies of IFN-g-expressing and CD107a-express cells in response to HBV stimulation. Together, our data demonstrated that the status of HBVspecific CD8(+) T cell exhaustion was associated with different clinical outcomes of chronic HBV infection.

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“…However, there is little evidence of such exhaustion occurring during CMV infection except in immune-compromised patients with high titers of replicating CMV [73,74]. Indeed, exhaustion appears to be a defined molecular program induced in T cells by some chronic infections [75], and gene expression profiles of HCMVspecific T cells do not conform to this molecular signature [38]. Notably, during chronic CMV infection in healthy humans and mice, CMV-specific T cells do not upregulate PD-1 [20,38], one inhibitory molecule that is strongly associated with antigen-driven T cell exhaustion.…”

Section: T Cell Exhaustion: a Paradigm For Several Chronic Infectionsmentioning

confidence: 99%

Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8+ T cells during cytomegalovirus infection

Snyder

2011

Immunol Res

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Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection

Cited by 1,382 publications

References 0 publications

T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract

T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract

Regulation of HBV-specific CD8+ T cell-mediated inflammation is diversified in different clinical presentations of HBV infection

Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8+ T cells during cytomegalovirus infection

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