IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection

Brooks, David G.; Ha, Sang Jun; Elsaesser, Heidi; Sharpe, Arlene H.; Freeman, Gordon J.; Oldstone, Michael B. A.

doi:10.1073/pnas.0811139106

Cited by 196 publications

(222 citation statements)

References 36 publications

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“…Multiple nonoverlapping factors seem to affect T cell exhaustion (35). Unexpectedly, we found that enhancement in polyfunctionality segregated with the presence of functionally intact DCs (Figs.…”

Section: Discussionmentioning

confidence: 71%

“…It is possible to block signaling through individual coinhibitory receptors, and the potential benefits of this strategy in controlling chronic viral infections have been discussed recently (7). By alleviating PD-L1-mediated inhibition in chronic infections, T cells are able to expand, thereby re-establishing high frequencies of existing polyfunctional virus-specific CD8 + T cells that can exert effective control over infection (35); this may not prove as beneficial when innate immune functions of DCs are impaired (40). In fact, in ongoing experiments we find that HCV-infected patients with a CP-N status have markedly improved viral control and enhanced SVR rates compared with CP-D patients on pegylated IFN-a and ribavirin therapy (I.G.…”

Section: Discussionmentioning

confidence: 99%

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

Rodrigue-Gervais

Rigsby

Jouan

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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

Rodrigue-Gervais

Rigsby

Jouan

et al. 2010

The Journal of Immunology

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“…More recently it was shown that blocking of multiple inhibitory receptors (PD-1, LAG-3, CTLA-4) [20] or the combined blocking of inhibitory receptors and immunosuppressive cytokines [59,104] is superior to blocking a single inhibitory receptor. In SIV-infected monkeys, in vivo blocking of PD-1 enhanced both cellular and humoral immune responses [61].…”

Section: T-cell Populationsmentioning

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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“…Although persistent LCMV infection is known to result from functional T cell exhaustion (reviewed in Ref. 181) associated with elevated PD-1 expression on T cells (182), as well as IL-10 and PD-L1 expression in infected mice (183,184), a role for type I IFNs in this process was poorly understood until recently.…”

Section: Lymphocytic Choriomeningitis Virusmentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

The Journal of Immunology

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Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

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IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection

Abstract: Suppression of T-cell responses by host-derived regulatory factors is

Cited by 196 publications

References 36 publications

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

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

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

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

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