Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming

Bénéchet, Alexandre P.; Simone, Giorgia De; Lucia, Pietro Di; Cilenti, Francesco; Barbiera, Giulia; Bert, Nina Le; Fumagalli, Valeria; Lusito, Eleonora; Moalli, Federica; Bianchessi, Valentina; Andreata, Francesco; Zordan, Paola; Bono, Elisa; Giustini, Leonardo; Bonilla, Weldy V.; Blériot, Camille; Kunasegaran, Kamini; González‐Aseguinolaza, Gloria; Pinschewer, Daniel D.; Kennedy, Patrick; Naldini, Luigi; Kuka, Mirela; Ginhoux, Florent; Cantore, Alessio; Bertoletti, Antonio; Ostuni, Renato; Guidotti, Luca G.; Iannacone, Matteo

doi:10.1038/s41586-019-1620-6

Cited by 155 publications

(221 citation statements)

References 71 publications

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“…In addition to T FH and Tregs, antiviral responders were also enriched for an intrahepatic M1 macrophage transcriptional signature. Mouse models have recently identified a central role for hepatic macrophages (Kupffer cells) in effective CD8 + T cell priming in the liver (22,23). For example, studies in an adoptive transfer model demonstrated that Kupffer cell-derived CXCL13 facilitates organization of CD8 + T cells, CD4 + T cells (including T FH ) and B cells in the liver, and that these lymphoid structures support intrahepatic immune priming (14,22).…”

Section: Accepted Articlementioning

confidence: 99%

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

et al. 2020

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GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 (TLR8) in clinical development for the treatment of chronic hepatitis B (CHB). In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus (HBV). WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688 or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells (PBMC) to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells (T FH) and various other immune cell subsets may play a role in the antiviral response to GS-9688. Conclusion: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks. The identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect. Approximately 260 million individuals are chronically infected with hepatitis B virus (HBV), and over half a million people are estimated to die each year due to liver diseases associated with chronic hepatitis B (CHB), such as cirrhosis and hepatocellular carcinoma (HCC). Immunological control of CHB ("functional cure") is defined as sustained loss of HBV surface antigen (HBsAg) off treatment, with or without seroconversion to anti-HBs antibody. Several nucleos(t)ide analogs, as well as interferon-alpha (IFN-α), are approved for the treatment of CHB. These therapies reduce viremia and

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Section: Accepted Articlementioning

confidence: 99%

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

et al. 2020

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“…T cell clustering was also observed in other anatomical sites, such as the liver [152]. Priming by Kupffer cells leads to the formation of dense, extravascular clusters of immotile cells and the development of effector cells.…”

Section: Regulation Of Effector Responsesmentioning

confidence: 83%

Modes of Communication between T Cells and Relevance for Immune Responses

Uhl

Gérard

2020

IJMS

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T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they differentiate into subsets required for short and long-term control of the pathogen, i.e., effector or memory. T cells have a remarkable degree of plasticity and heterogeneity in their response, however, their overall response to a given infection is consistent and robust. Much research has focused on how individual T cells are activated and programmed. However, in order to achieve a critical level of population-wide reproducibility and robustness, neighbouring cells and surrounding tissues have to provide or amplify relevant signals to tune the overall response accordingly. The characteristics of the immune response—stochastic on the individual cell level, robust on the global level—necessitate coordinated responses on a system-wide level, which facilitates the control of pathogens, while maintaining self-tolerance. This global coordination can only be achieved by constant cellular communication between responding cells, and faults in this intercellular crosstalk can potentially lead to immunopathology or autoimmunity. In this review, we will discuss how T cells mount a global, collective response, by describing the modes of T cell-T cell (T-T) communication they use and highlighting their physiological relevance in programming and controlling the T cell response.

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“…Indeed, a beneficial effect of PD-1 blockade on therapeutic vaccination is observed in the LCMV mouse model and in woodchucks infected with HBV (101,102). Moreover, HBV-specific T cells that were induced by dendritic cells are more responsive to PD-1 blockade when compared to those T cells primed by hepatocytes in HBV replication-competent transgenic mice (103). These synergistic effects did, however, not results into a clinical benefit in a small pilot study that administered nivolumab and a therapeutic vaccine to ten virally suppressed chronic HBV patients (83).…”

Section: Therapeutic Vaccinesmentioning

confidence: 99%

Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection

Hoogeveen

Boonstra

2020

Front. Immunol.

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Treatment of chronic hepatitis B virus (HBV) infection is highly effective in suppressing viral replication, but complete cure is rarely achieved. In recent years, substantial progress has been made in the development of immunotherapy to treat cancer. Applying these therapies to improve the management of chronic HBV infection is now being attempted, and has become an area of active research. Immunotherapy with vaccines and checkpoint inhibitors can boost T cell functions in vitro, and therefore may be used to reinvigorate the impaired HBV-specific T cell response. However, whether these approaches will suffice and restore antiviral T cell immunity to induce long-term HBV control remains an open question. Recent efforts have begun to describe the phenotype and function of HBV-specific T cells on the single epitope level. An improved understanding of differing T cell specificities and their contribution to HBV control will be instrumental for advancement of the field. In this review, we outline correlates of successful versus inadequate T cell responses to HBV, and discuss the rationale behind therapeutic vaccines and checkpoint inhibitors for the treatment of chronic HBV infection.

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Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming

Cited by 155 publications

References 71 publications

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B

Modes of Communication between T Cells and Relevance for Immune Responses

Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection

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