In vivo expression of perforin by CD8+ lymphocytes during an acute viral infection.

Young, Lucy H.; Klavinskis, Linda; Oldstone, M B; Young, John Ding‐E

doi:10.1084/jem.169.6.2159

Cited by 91 publications

(29 citation statements)

References 39 publications

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“…Indeed, the results are consistent with a model in which CD8 + T cells are the key cellular effectors mediating HBV clearance from the liver, and in which CD4 + T cells, NK cells, Fas, IFN-γ, IFN-α/βR, and TNFR1 contribute to the induction of the antiviral CD8 + T cell response and elimination of HBV-positive hepatocytes. Surprisingly, although clearance of this plasmid, like clearance of cccDNA, is likely to be a cytodestructive process, it did not require perforin, the major cytolytic mediator in CD8 + T cells (26). Because the input plasmid persisted for the duration of the study in Fas-and TNFR1-deficient animals, the data suggest that, unexpectedly, one or both of those pathways may play a role in elimination of the natural cccDNA transcriptional template during natural HBV infection in man.…”

Section: Resultsmentioning

confidence: 99%

Immune effectors required for hepatitis B virus clearance

Yang

Althage

Chung

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

182

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To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4 + and CD8 + T cells, NK cells, Fas, IFN-gamma (IFN-γ), IFN-alpha/beta receptor (IFN-α/βR1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8 + T cell response in these animals depended on the presence of CD4 + T cells. These results are consistent with a model in which CD4 + T cells serve as master regulators of the adaptive immune response to HBV; CD8 + T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforinindependent process in which NK cells, IFN-γ, TNFR1, and IFN-α/βR play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.H epatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute and chronic hepatitis and hepatocellular carcinoma (1). Approximately 350 million people worldwide are chronically infected by HBV, which greatly increases the risk of hepatocellular carcinoma (HCC) and causes more than 1 million deaths annually (2). Because HBV is not infectious in small animal or tissue culture models, systematic examination of the host-virus interactions during HBV infection has been difficult. The full spectrum of immunological requirements for HBV clearance is not completely defined.Our current understanding is based to a large extent on comparison of the immune responses mounted against HBV in patients who clear and who fail to clear HBV (3), experiments in which potential effectors of clearance (e.g., HBsAg-specific CD8 + T cells, recombinant IFN-γ and TNF-α) have been adoptively transferred to or induced in HBV transgenic mice (4-8), and a limited number of experiments conducted in HBVinfected chimpanzees (9, 10, 18). Collectively, these studies have led to the current model for clearance of acute HBV infection, namely (i) that viral clearance during HBV infection is associated with entry of CD8 + T cells into the liver, the production of IFN-γ, and the induction of inflammatory liver disease (reviewed in ref.3); (ii) that IFN-γ production, viral clearance, and liver disease are all impaired in the absence of CD8 + T cells (11); and (iii) that noncy...

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Section: Resultsmentioning

confidence: 99%

Immune effectors required for hepatitis B virus clearance

Yang

Althage

Chung

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

182

View full text Add to dashboard Cite

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“…In functional terms, such cells share features of both CD28 ϩ and CD28 Ϫ cells. IFN-␥ production during a short term assay (25,28) and the presence of intracellular perforin granules ex vivo both point to their effector potential (36,37). Indeed, they exert a potent cytolytic activity in a CD3-redirected assay, which mimics Agspecific cytotoxicity in vitro (38).…”

Section: Discussionmentioning

confidence: 99%

CD11b Expression Identifies CD8+CD28+ T Lymphocytes with Phenotype and Function of Both Naive/Memory and Effector Cells

Fiorentini

Licenziati

Alessandri

et al. 2001

The Journal of Immunology

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A previously unreported CD8+CD28+CD11b+ T cell subset occurs in healthy individuals and expands in patients suffering from primary viral infections. In functional terms, these cells share the features of naive/memory CD8+CD28+CD11b− and terminally differentiated effector CD8+CD28−CD11b+ subpopulations. Like CD28− cells, CD28+CD11b+ lymphocytes have the ability to produce IFN-γ, to express perforin granules in vivo, and to exert a potent cytolytic activity. Moreover, these cells can respond to chemotactic stimuli and can efficiently cross the endothelial barrier. In contrast, like their CD11b− counterpart, they still produce IL-2 and retain the ability to proliferate following mitogenic stimuli. The same CD28+CD11b+ subpopulation detected in vivo could be generated by culturing naive CD28+CD11b− cells in the presence of mitogenic stimuli following the acquisition of a CD45RO+ memory phenotype. Considering both phenotypic and functional properties, we argue that this subset may therefore constitute an intermediate phenotype in the process of CD8+ T cell differentiation and that the CD11b marker expression can distinguish between memory- and effector-type T cells in the human CD8+CD28+ T cell subset.

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“…Other functions, not directly related to cellmediated cytotoxicity, such as an involvement in B cell activation or degradation of extracellular matrix (7), were also proposed for serine proteases in T lymphocytes. In vivo, the majority of the perforin-and granzyme-containing CTL seem to be of the CD4-CD8+ phenotype (8)(9)(10)(11), although a minor fraction of Thy-1 + CD4 + CD8-peripheral T cells also express the granzyme A gene in vivo (8).…”

Section: Introductionmentioning

confidence: 99%