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Relatively little is known about immune evasion during the productive phase of infection by the γ₁-herpesvirus Epstein-Barr virus (EBV). The use of a unique system to isolate cells in lytic cycle allowed us to identify a host shutoff function operating in productively EBV-infected B cells. This impairment of protein synthesis results from mRNA degradation induced upon expression of the early lytic-cycle gene product BGLF5. Recently, a γ₂-herpesvirus, Kaposi sarcoma herpesvirus, has also been shown to encode a host shutoff function, indicating that host shutoff appears to be a general feature of γ-herpesviruses. One of the consequences of host shutoff is a block in the synthesis of HLA class I and II molecules, reflected by reduced levels of these antigen-presenting complexes at the surface of cells in EBV lytic cycle. This effect could lead to escape from T cell recognition and elimination of EBV-producing cells, thereby allowing generation of viral progeny in the face of memory T cell responses.

Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies. We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC), as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras). Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation. Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines. Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer.

Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration. Selective neurodegeneration is a critical causal factor in Alzheimer’s disease. Zalocusky et al. demonstrate a causal chain linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

The cytokine interferon-γ (IFNγ) is a central coordinator of innate and adaptive immunity, but its highly pleiotropic actions have diminished its prospects for use as an immunotherapeutic agent. Here, we took a structure-based approach to decoupling IFNγ pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNγ receptor IFNγR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNγ–IFNγR1–IFNγR2 signalling complex at 3.25 Å resolution. The structure reveals the mechanism underlying deficits in IFNγ responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNγR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNγ variants to tune IFNγ receptor signalling output. Unexpectedly, we found that several partial IFNγ agonists exhibited biased gene-expression profiles. These biased agonists retained the ability to induce upregulation of major histocompatibility complex class I antigen expression, but exhibited impaired induction of programmed death-ligand 1 expression in a wide range of human cancer cell lines, offering a route to decoupling immunostimulatory and immunosuppressive functions of IFNγ for therapeutic applications. The X-ray structure of the hexameric complex of interferon-γ bound to its receptors is solved at 3.25 Å resolution, providing a basis for engineering variants of interferon-γ that enable decoupling of its immunomodulatory functions.

Expression of MHC class I molecules on motor neurons protects them from astrocyte-induced toxicity in ALS. Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.

Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechip ® technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex (MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo . Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT-PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for β 2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo , respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a ‘stealth’-like manner.

Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I) expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β) and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo- (or radio-)/immuno-therapy.

Background: Major histocompatibility complex (MHC) class I chain-related protein A (MICA) and MHC class I chain-related protein B (MICB) are polymorphic proteins that are induced upon stress, damage or transformation of cells which act as a ‘kill me’ signal through the natural-killer group 2, member D receptor expressed on cytotoxic lymphocytes. MICA/B are not thought to be constitutively expressed by healthy normal cells but expression has been reported for most tumour types. However, it is not clear how much of this protein is expressed on the cell surface. Methods: Using a novel, well-characterised antibody and both standard and confocal microscopy, we systematically profiled MICA/B expression in multiple human tumour and normal tissue. Results: High expression of MICA/B was detected in the majority of tumour tissues from multiple indications. Importantly, MICA/B proteins were predominantly localised intracellularly with only occasional evidence of cell membrane localisation. MICA/B expression was also demonstrated in most normal tissue epithelia and predominantly localised intracellularly. Crucially, we did not observe qualitative differences in cell surface expression between tumour and MICA/B expressing normal epithelia. Conclusions: This demonstrates for the first time that MICA/B is more broadly expressed in normal tissue and that expression is mainly intracellular with only a small fraction appearing on the cell surface of some epithelia and tumour cells.

The p53 tumour suppressor has an important role in cancer cells. Here we show that p53 regulates expression of major histocompatibility complex I on the cell surface. We show that the tumour cell line HCT116, which lacks p53 exhibits significantly lower major histocompatibility complex I expression than its wild-type counterpart. Using a combination of chromatin immunoprecipitation sequencing and gene expression analysis, we demonstrate that p53 upregulates expression of endoplasmic reticulum aminopeptidase 1 by binding to its cognate response element in the ERAP1 gene. Silencing of p53 decreases endoplasmic reticulum aminopeptidase 1 protein levels and therefore major histocompatibility complex I expression. We further show that this mechanism operates in A549 cells infected with H1N1 influenza virus, in which H1N1 activates p53, leading to endoplasmic reticulum aminopeptidase 1 upregulation and a corresponding increase in major histocompatibility complex I expression. Our study suggests a previously unrecognized link between p53 function and the immunosurveillance of cancer and infection. The protein p53 is an important tumour suppressor. Here Wang et al. show that p53 can induce expression of MHC class I on the cell surface by promoting expression of the aminopeptidase ERAP1, and that this mechanism operates in cancer cells as well as those infected with influenza virus.

In recent years, immunotherapy has proven to be an effective treatment against cancer. Cytotoxic T lymphocytes perform an important role in this anti-tumor immune response, recognizing cancer cells as foreign, through the presentation of tumor antigens by MHC class I molecules. However, tumors and metastases develop escape mechanisms for evading this immunosurveillance and may lose the expression of these polymorphic molecules to become invisible to cytotoxic T lymphocytes. In other situations, they may maintain MHC class I expression and promote immunosuppression of cytotoxic T lymphocytes. Therefore, the analysis of the expression of MHC class I molecules in tumors and metastases is important to elucidate these escape mechanisms. Moreover, it is necessary to determine the molecular mechanisms involved in these alterations to reverse them and recover the expression of MHC class I molecules on tumor cells. This review discusses the role and regulation of MHC class I expression in tumor progression. We focus on altered MHC class I phenotypes present in tumors and metastases, as well as the molecular mechanisms responsible for MHC-I alterations, emphasizing the mechanisms of recovery of the MHC class I molecules expression on cancer cells. The individualized study of the HLA class I phenotype of the tumor and the metastases of each patient will allow choosing the most appropriate immunotherapy treatment based on a personalized medicine.