Visualizing Antigen-Specific and Infected Cells in Situ Predicts Outcomes in Early Viral Infection

Li, Qingsheng; Skinner, Pamela J.; Ha, Sang Jun; Duan, Lijie; Mattila, Teresa L.; Hage, Aaron; White, Cara; Barber, Daniel L.; O'Mara, Leigh A.; Southern, Peter J.; Reilly, Cavan; Carlis, John V.; Miller, Christopher J.; Ahmed, Rafi; Haase, Ashley T.

doi:10.1126/science.1168676

Cited by 174 publications

(182 citation statements)

References 20 publications

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“…During MHV68 infection, plasmacytoid dendritic cells are recruited to the lung and upregulate major histocompatibility complex (MHC) class II (40 (45). High levels of antigen exposure are key mediators of CD8 ϩ T cell exhaustion (46)(47)(48). In support of this mechanism, early mitigation of MHV68 replication in IFNAR1 Ϫ/Ϫ mice resulted in marked improvement in CD8 ϩ T cell TNF-␣ and IFN-␥ production, as well as reduced PD-1 expression.…”

Section: Ifnar1mentioning

confidence: 80%

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Jennings

Grayson

Barton

2014

J Virol

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CD8؉ T cell responses are critical to the control of replication and reactivation associated with gammaherpesvirus infection. Type I interferons (IFNs) have been shown to have direct and indirect roles in supporting CD8؉ T cell development and function during viral infection; however, the role of type I interferons during latent viral infection has not been examined. Mice deficient in type I IFN signaling (IFNAR1 ؊/؊ mice) have high levels of reactivation during infection with murine gammaherpesvirus 68 (MHV68), a murine gammaherpesvirus model for Epstein-Barr virus. We hypothesized that type I IFNs function to enhance the anti-gammaherpesvirus CD8 ؉ T cell response. To test this, IFNAR1 ؊/؊ mice were infected with MHV68 and the CD8 ؉ T cell response was analyzed. In the absence of type I IFN signaling, there was a marked increase in short-lived effector CD8 ؉ T cells, and MHV68-specific CD8 ؉ T cells had upregulated expression of PD-1 and reduced tumor necrosis factor alpha (TNF-␣), gamma IFN (IFN-␥), and interleukin-2 (IL-2) production. Suppressing MHV68 replication early in infection using the antiviral cidofovir rescued CD8 ؉ T cell cytokine production and reduced PD-1 expression. However, suppressing high levels of reactivation in IFNAR1؊/؊ mice failed to improve CD8 ؉ T cell cytokine production during latency. T cell-specific abrogation of type I IFN signaling showed that the effects of type I IFNs on the CD8 ؉ T cell response during MHV68 infection are independent of direct type I IFN signaling on T cells. Our findings support a model in which type I IFNs likely suppress MHV68 replication, thus limiting viral antigen and facilitating an effective gammaherpesvirus-directed CD8 ؉ T cell response. IMPORTANCE The murine gammaherpesvirus MHV68 has both genetic and biologic homology to the human gammaherpesvirus Epstein-Barr virus (EBV), which infects over 90% of humans. Latent EBV infection and reactivation are associated with various life-threatening diseases and malignancies. Host suppression of gammaherpesvirus latency and reactivation requires both CD8 T he gammaherpesvirus-directed CD8ϩ T cell response is critical to the control of replication and reactivation associated with Epstein-Barr virus (EBV) infection, and individuals with either genetic or acquired immunodeficiencies are highly susceptible to EBV-associated diseases (1-3). Adoptive transfer of EBVspecific CD8 ϩ T cells has been successfully utilized to treat EBVassociated lymphoproliferative disease (4, 5). In addition, CD8 ϩ T cells prevent in vivo tumor outgrowth of B cell cancer lines immortalized by murine gammaherpesvirus 68 (MHV68), a wellcharacterized virus model for EBV (6). Thus, CD8ϩ T cells can suppress gammaherpesvirus-associated malignancies. The promise of immunotherapy and vaccine development relies on our understanding of factors that promote a highly effective gammaherpesvirus-directed CD8 ϩ T cell response. CD8 ϩ T cells responding to their cognate antigen require three signals for survival and differentiation: antige...

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Section: Ifnar1mentioning

confidence: 80%

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Jennings

Grayson

Barton

2014

J Virol

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“…Recently, a combined in situ tetramer staining and in situ hybridization approach showed that relative rates of increase in Agspecific effector CD8 + T cells and virally infected targets during the early stage predict the outcome of viral infection (56). For example, LCMV clone 13 preferentially infects fibroblastic reticular cells, which enables this clone to spread and replicate tremendously faster than LCMV-Armstrong, thereby exceeding the capacity of initial immune response to reduce the basic rate of replication.…”

Section: Discussionmentioning

confidence: 99%

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

Takamura¹,

Tsuji-Kawahara²,

Yagita

et al. 2010

The Journal of Immunology

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During chronic viral infection, persistent exposure to viral Ags leads to the overexpression of multiple inhibitory cell-surface receptors that cause CD8+ T cell exhaustion. The severity of exhaustion correlates directly with the level of infection and the number and intensity of inhibitory receptors expressed, and it correlates inversely with the ability to respond to the blockade of inhibitory pathways. Friend virus (FV) is a murine retrovirus complex that induces acute high-level viremia, followed by persistent infection and leukemia development, when inoculated into immunocompetent adult mice. In this article, we provide conclusive evidence that FV infection results in the generation of virus-specific effector CD8+ T cells that are terminally exhausted. Acute FV-induced disease is characterized by a rapid increase in the number of virus-infected erythroblasts, leading to massive splenomegaly. Most of the expanded erythroblasts strongly express programmed death ligand-1 and MHC class I, thereby creating a highly tolerogenic environment. Consequently, FV-specific effector CD8+ T cells uniformly express multiple inhibitory receptors, such as programmed cell death 1 (PD-1), T cell Ig domain and mucin domain 3 (Tim-3), lymphocyte activation gene-3, and CTLA-4, rapidly become nonresponsive to restimulation and are no longer reinvigorated by combined in vivo blockade of PD-1 and Tim-3 during the memory phase. However, combined blockade of PD-1 and Tim-3 during the priming/differentiation phase rescued FV-specific CD8+ T cells from becoming terminally exhausted, resulting in improved CD8+ T cell functionality and virus control. These results highlight FV’s unique ability to evade virus-specific CD8+ T cell responses and the importance of an early prophylactic approach for preventing terminal exhaustion of CD8+ T cells.

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“…These types of infections often lead to high levels of virus-derived peptide antigens presented by MHC class I molecules on a variety of infected cell types, depending on the tropism of the virus. Exhaustion of antiviral CD8 1 T cells occurs rapidly and extensively in chronic LCMV infection, which is likely attributable to the fact that LCMV infects in vivo a large variety of hematopoietic as well as non-hematopoietic cells and therefore leads to high antigen burden perceived by LCMVspecific CD8 1 T cells [70,78]. Exhaustion of HIV-specific CD8…”

Section: Antigen Loadmentioning

confidence: 99%

How chronic viral infections impact on antigen‐specific T‐cell responses

2010

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Persistent viral infections are, by definition, associated with ineffective antiviral immunity, in particular those infections caused by viruses that are highly productive and replicative (including HIV, HBV and HCV). The reasons for ineffective antiviral immunity in these types of infections are complex and manifold, and only recently a more comprehensive picture of the parameters responsible for attenuation of immune function is emerging. One reason for poor viral control in these types of infections is the functional deterioration of antiviral T-cell responses and understanding the underlying mechanisms is of key importance. This review summarizes our current knowledge of cell-intrinsic and cellextrinsic parameters that contribute to T-cell exhaustion during chronic viral infections and discusses related implications for host survival, immunopathology, and control of infection. Key words: Persistent viral infection . T-cell dysfunction . T-cell immunity IntroductionPersistent viral infections, by definition, are not entirely controlled by the host's immune system and are often associated with relevant clinical disease outcomes. Persistent viral infections can be roughly divided into (i) highly productive and replicative infections (associated with continued high abundance of viral antigens) and (ii) latent/reactivating infections (associated with low and perhaps sporadic levels of viral antigens). Well-known examples of the former are HIV, HBV and HCV, which together infect more than 2 billion people worldwide (http://www. unaids.org/; http://www.epidemic.org/; http://www.hepb.org/), and lymphocytic choriomeningitis virus (LCMV) infection in the mouse. Examples of the latter are herpes virus infections, including EBV, CMV, and HSV, which affect together almost 100% of the population. Viruses falling into these two categories have evolved very diverse strategies for co-existence in an immunocompetent host. Highly productive and replicative viruses tend to induce impaired virus-specific adaptive immune responses, which are characterized by limited and dysfunctional T-cell responses, and mutational escape from immune (or drug) pressure are common features of these viruses. Viruses causing latent/reactivating infections have, as a result of their large coding capacity, evolved strategies to interfere with host immunity (immune evasion mechanisms) and have acquired genetic programs that permit a latent, non-replicative existence of the viral genetic information with the option of resuming viral replication in response to certain stimuli. These viral reactivation events, however, are generally well controlled by host immunity and only become clinically apparent in circumstances of immunosuppression.This review focuses on highly productive and replicative persistent viral infections (hereafter referred to as persistent viral infection) with specific emphasis on cell-intrinsic and -extrinsic mechanisms responsible for constraining the size of the antiviral T-cell response and for T-cell dysfunction (summarized in Fig...

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Visualizing Antigen-Specific and Infected Cells in Situ Predicts Outcomes in Early Viral Infection

Cited by 174 publications

References 20 publications

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

How chronic viral infections impact on antigen‐specific T‐cell responses

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Visualizing Antigen-Specific and Infected Cells in Situ Predicts Outcomes in Early Viral Infection

Cited by 174 publications

References 20 publications

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Type I Interferon Signaling Enhances CD8+T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

How chronic viral infections impact on antigen‐specific T‐cell responses

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Product

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Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection

Type I Interferon Signaling Enhances CD8⁺T Cell Effector Function and Differentiation during Murine Gammaherpesvirus 68 Infection