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Liver sinusoidal endothelial cells (LSECs) line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen (cross)-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.

Key Points The liver serves as an important filter organ to remove circulating pathogens from the blood. However, certain pathogens — such as hepatitis B virus, hepatitis C virus and malaria-inducing Plasmodium spp. parasites — efficiently target the liver and can establish persistent infections in hepatocytes. Despite the function of the liver in skewing immune responses towards tolerance, hepatic cells are equipped with innate immune sensory receptors to detect infectious microorganisms and mount inflammatory responses. Most infectious microorganisms are cleared from the liver through the combination of innate and adaptive immune defence, despite pathogen-specific immune escape strategies. However, our knowledge on the decisive molecular mechanisms that discriminate acute, resolving infections from chronic infections is still incomplete. Persistent infection of hepatocytes is perpetuated by the immunoregulatory liver microenvironment, the predominant co-inhibitory over co-stimulatory signalling by hepatic antigen-presenting cells and the exhaustion of pathogen-specific T cells. Novel therapeutic strategies to overcome chronic viral infection of hepatocytes will combine measures to lower the level of viral antigens in combination with measures to increase the number of virus-specific T cells and their efficiency to locally exert their effector function in the liver. The tolerogenic properties of the liver make it an attractive site for infection by pathogens. This Review describes how most pathogens are effectively controlled by immune responses in the liver, and how some pathogens, such as hepatitis viruses and malaria-causing parasites, can establish chronic infections in the liver. The liver has vital metabolic and clearance functions that involve the uptake of nutrients, waste products and pathogens from the blood. In addition, its unique immunoregulatory functions mediated by local expression of co-inhibitory receptors and immunosuppressive mediators help to prevent inadvertent organ damage. However, these tolerogenic properties render the liver an attractive target site for pathogens. Although most pathogens that reach the liver via the blood are eliminated or controlled by local innate and adaptive immune responses, some pathogens (such as hepatitis viruses) can escape immune control and persist in hepatocytes, causing substantial morbidity and mortality worldwide. Here, we review our current knowledge of the mechanisms of liver targeting by pathogens and describe the interplay between pathogens and host factors that promote pathogen elimination and maintain organ integrity or that allow pathogen persistence.

Key Points The liver is a solid organ with unique immunoregulatory functions that are determined by the hepatic microenvironment, which is rich in regulatory soluble mediators, and by local antigen-presenting cells (APCs) with tolerogenic capabilities located within a unique anatomical microarchitecture. Local hepatic APCs with tolerogenic function are myeloid and plasmacytoid dendritic cells, liver sinusoidal endothelial cells, Kupffer cells and hepatocytes. Under steady-state conditions, these cells induce T cell tolerance by numerous mechanisms, including clonal elimination, the induction of T cell anergy and the induction, recruitment or proliferation of regulatory T (T Reg ) cells. Tolerogenic hepatic APCs characteristically resist functional maturation in response to pathogen- or danger-associated molecular patterns (PAMPs; DAMPs), which are present physiologically in portal venous blood, through the development of hyporesponsiveness towards these stimuli or through non-responsiveness due to cell-intrinsic regulatory mechanisms. Microbial infection leading to the functional maturation of tolerogenic into immunogenic APCs, either by cell-autonomous mechanisms or cell–cell interactions, can result in the local induction of T cell immunity in the liver by mechanisms that still need to be defined. The abundance of tolerogenic APCs within the hepatic sinusoids facilitates interaction with circulating T cells and allows the liver to function as a large immunoregulatory platform aimed at skewing hepatic, as well as extrahepatic, immune responses. The principles governing hepatic tolerance or immunity may be exploited to develop therapeutic options to mitigate autoimmunity or allograft rejection, to prolong hepatic transgene expression or to overcome tolerogenic barriers in persistent infection and cancer. The mechanisms by which local antigen-presenting cells, such as myeloid and plasmacytoid dendritic cells, liver sinusoidal endothelial cells, Kupffer cells and hepatocytes, mediate tolerance to antigens metabolized in the liver are described here. These insights into hepatic tolerance may be harnessed in the clinic for the treatment of various diseases. The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and non-parenchymal antigen-presenting cells (APCs), cell-autonomous molecular pathways and locally produced factors. Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy.

Non-alcoholic fatty liver disease (NAFLD) has emerged pandemically across the globe and particularly affects patients with obesity and type 2 diabetes. NAFLD is a complex systemic disease that is characterised by hepatic lipid accumulation, lipotoxicity, insulin resistance, gut dysbiosis and inflammation. In this review, we discuss how metabolic dysregulation, the gut microbiome, innate and adaptive immunity and their interplay contribute to NAFLD pathology. Lipotoxicity has been shown to instigate liver injury, inflammation and insulin resistance. Synchronous metabolic dysfunction, obesity and related nutritional perturbation may alter the gut microbiome, in turn fuelling hepatic and systemic inflammation by direct activation of innate and adaptive immune responses. We review evidence suggesting that, collectively, these unresolved exogenous and endogenous cues drive liver injury, culminating in liver fibrosis and advanced sequelae of this disorder such as liver cirrhosis and hepatocellular carcinoma. Understanding NAFLD as a complex interplay between metabolism, gut microbiota and the immune response will challenge the clinical perception of NAFLD and open new therapeutic avenues. Tilg et al. explore how metabolic dysfunction, altered gut microbiome and dysregulated innate and adaptive immunity contribute to NAFLD and how the interplay between these factors mediates disease progression.

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential 1 – 4 . This process, known as T cell exhaustion or dysfunction 1 , is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1) 5 – 8 . The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood 9 – 12 . Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein 13 – 15 . TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1 + self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology. TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infections.

Changes of mRNA 3’UTRs by alternative polyadenylation (APA) have been associated to numerous pathologies, but the mechanisms and consequences often remain enigmatic. By combining transcriptomics, proteomics and recombinant viruses we show that all tested strains of IAV, including A/PR/8/34(H1N1) (PR8) and A/Cal/07/2009 (H1N1) (Cal09), cause APA. We mapped the effect to the highly conserved glycine residue at position 184 (G184) of the viral non-structural protein 1 (NS1). Unbiased mass spectrometry-based analyses indicate that NS1 causes APA by perturbing the function of CPSF4 and that this function is unrelated to virus-induced transcriptional shutoff. Accordingly, IAV strain PR8, expressing an NS1 variant with weak CPSF binding, does not induce host shutoff but only APA. However, recombinant IAV (PR8) expressing NS1(G184R) lacks binding to CPSF4 and thereby also the ability to cause APA. Functionally, the impaired ability to induce APA leads to an increased inflammatory cytokine production and an attenuated phenotype in a mouse infection model. Investigating diverse viral infection models showed that APA induction is a frequent ability of many pathogens. Collectively, we propose that targeting of the CPSF complex, leading to widespread alternative polyadenylation of host transcripts, constitutes a general immunevasion mechanism employed by a variety of pathogenic viruses. Here, Bergant et al. provide evidence that Influenza A viruses cause alternative polyadenylation of host mRNAs and abrogation of this function leads to an attenuated phenotype in mice. This may constitute a general immune evasive mechanism employed by a variety of pathogenic viruses.

Cancer-specific TCF1 + stem-like CD8 + T cells can drive protective anticancer immunity through expansion and effector cell differentiation 1 – 4 ; however, this response is dysfunctional in tumours. Current cancer immunotherapies 2 , 5 – 9 can promote anticancer responses through TCF1 + stem-like CD8 + T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1 + CD8 + T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE 2 ) restricts the proliferative expansion and effector differentiation of TCF1 + CD8 + T cells within tumours, which promotes cancer immune escape. PGE 2 does not affect the priming of TCF1 + CD8 + T cells in draining lymph nodes. PGE 2 acts through EP 2 and EP 4 (EP 2 /EP 4 ) receptor signalling in CD8 + T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1 + tumour-infiltrating CD8 + T lymphocytes (TILs). Ablation of EP 2 /EP 4 signalling in cancer-specific CD8 + T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE 2 -mediated inhibition of TCF1 + TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1 + TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE 2 –EP 2 /EP 4 axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control. Tumour-derived prostaglandin E 2 , signaling through its receptors EP 2 and EP 4 , is shown to restrain the responses of tumour-infiltrating stem-like TCF1 + CD8 + T lymphocytes, and modulation of T cell EP 2 and EP 4 can restore anticancer immunity.

Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-κB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB- and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer 1 , 2 . The accumulation of metabolites leads to cell stress and inflammation in the liver 3 , but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6 + CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6 + CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6 + CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity. Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .

Infection-neutralizing antibody responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 vaccination are an essential component of antiviral immunity. Antibody-mediated protection is challenged by the emergence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529), which is rapidly spreading worldwide. Here we report neutralizing antibody dynamics in a longitudinal cohort of coronavirus disease 2019 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying SARS-CoV-2 spike protein antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron. High levels of neutralizing antibodies are successfully elicited against SARS-CoV-2 variants of concern, including omicron, after three exposures to the viral spike protein, mediated by vaccination with BNT162b2 alone or by a combination of vaccination and infection.