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Specialized subpopulations of CD4 + T cells survey major histocompatibility complex class II–peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4 + T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4 + T cell biology. In this Review, Künzli and Masopust provide updates on our understanding of the biology of memory CD4 + T cells as well as key technological advances that facilitate their characterization.

Hepatitis B virus (HBV) is a non-cytopathic, hepatotropic virus with the potential to cause a persistent infection, ultimately leading to cirrhosis and hepatocellular carcinoma. Over the past four decades, the basic principles of HBV gene expression and replication as well as the viral and host determinants governing infection outcome have been largely uncovered. Whereas HBV appears to induce little or no innate immune activation, the adaptive immune response mediates both viral clearance as well as liver disease. Here, we review our current knowledge on the immunobiology and pathogenesis of HBV infection, focusing in particular on the role of CD8+ T cells and on several recent breakthroughs that challenge current dogmas. For example, we now trust that HBV integration into the host genome often serves as a relevant source of hepatitis B surface antigen (HBsAg) expression during chronic infection, possibly triggering dysfunctional T cell responses and favouring detrimental immunopathology. Further, the unique haemodynamics and anatomy of the liver — and the changes they frequently endure during disease progression to liver fibrosis and cirrhosis — profoundly influence T cell priming, differentiation and function. We also discuss why therapeutic approaches that limit the intrahepatic inflammatory processes triggered by HBV-specific T cells might be surprisingly beneficial for patients with chronic infection.In this Review, Iannacone and Guidotti discuss the immunobiology and pathogenesis of hepatitis B virus (HBV) infection, with a particular focus on the role of CD8+ T cells, and examine recent breakthroughs that challenge current dogmas.

Key Points The type I interferon (IFN) system involves a single form of IFNβ, several variants of IFNα and other less well-characterized IFNs, all of which signal via a heterodimeric IFNα/β receptor 1 (IFNAR1)–IFNAR2 receptor to transactivate IFN-stimulated genes (ISGs). IFNβ also promotes the transactivation of ISGs through homodimeric IFNAR1. The secretion of type I IFNs is stimulated by viral constituents, as well as by danger signals emitted by dying cells, including nuclear and mitochondrial nucleic acids found at ectopic locations. The production of type I IFNs has marked antiviral and immunostimulatory effects. Beyond their role in curtailing viral infection, type I IFNs play an essential part in natural cancer immunosurveillance, functioning both at the level of malignant cell precursors and through effects on the immune system. Thus, the knockout of Ifnar1 in mouse epithelial cells predisposes them to malignant transformation, as does the knockout of Ifnar1 in leukocytes, especially dendritic cells. Type I IFN signalling is also essential for the full-blown efficacy of various anticancer agents, including chemotherapeutics (such as anthracyclines), antibodies that target growth factor receptors (such as human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR)), the injection of adjuvants and oncolytic virotherapy. The expression levels of ISGs constitute a positive prognostic or predictive biomarker in patients affected by several cancers including melanoma and breast carcinoma. Recombinant type I IFNs have been successfully used for the treatment of various human neoplasms, particularly ulcerative melanoma, renal cell carcinoma and hepatitis B virus (HBV)-induced hepatocellular carcinoma. Preclinical data identify four distinct approaches to improve the targeted delivery of type I IFNs to malignant lesions: first, fusing or linking recombinant type I IFNs to antibodies specific for tumour-associated surface antigens; second, engineering leukocytes or mesenchymal stem cells to express type I IFNs once they have infiltrated neoplastic lesions; third, injecting type I IFN-encoding vectors into the tumour mass; and fourth, supplying artificial ligands of type I IFN-stimulating pattern recognition receptors (PRRs). Type I interferons (IFNs) are best known for their role in antiviral immunity. As discussed in this Review, recent evidence indicates that these cytokines also have an integral role in natural and therapy-induced anticancer immunity. Harnessing the antineoplastic properties of type I IFNs may lead to the development of ever-more effective anticancer therapies. Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with favourable disease outcome in several cohorts of patients with cancer. Finally, new anticancer immunotherapies are being developed that are based on recombinant type I IFNs, type I IFN-encoding vectors and type I IFN-expressing cells.

Lethal hit delivery by cytotoxic T lymphocytes (CTL) towards B lymphoma cells occurs as a binary, “yes/no” process. In non-hematologic solid tumors, however, CTL often fail to kill target cells during 1:1 conjugation. Here we describe a mechanism of “additive cytotoxicity” by which time-dependent integration of sublethal damage events, delivered by multiple CTL transiting between individual tumor cells, mediates effective elimination. Reversible sublethal damage includes perforin-dependent membrane pore formation, nuclear envelope rupture and DNA damage. Statistical modeling reveals that 3 serial hits delivered with decay intervals below 50 min discriminate between tumor cell death or survival after recovery. In live melanoma lesions in vivo, sublethal multi-hit delivery is most effective in interstitial tissue where high CTL densities and swarming support frequent serial CTL-tumor cell encounters. This identifies CTL-mediated cytotoxicity by multi-hit delivery as an incremental and tunable process, whereby accelerating damage magnitude and frequency may improve immune efficacy. Cytotoxic CD8 + T lymphocytes (CTL) often fail to kill tumour cells in one-to-one interactions. Here the authors show that these sublethal interactions from multiple CTL can add up over time and achieve tumour cell killing by additive cytotoxicity.

Immune responses in tissues are constrained by the physiological properties of the tissue involved. Tissue-resident memory T cells (T RM cells) are a recently discovered lineage of T cells specialized for life and function within tissues. Emerging evidence has shown that T RM cells have a special role in the control of solid tumors. A high frequency of T RM cells in tumors correlates with favorable disease progression in patients with cancer, and studies of mice have shown that T RM cells are necessary for optimal immunological control of solid tumors. Here we describe what defines T RM cells as a separate lineage and how these cells are generated. Furthermore, we discuss the properties that allow T RM cells to operate in normal and transformed tissues, as well as implications for the treatment of patients with cancer. Tissue-resident memory T cells provide immunological protection in peripheral tissues. Amsen et al . discuss the role of these cells in the context of anti-tumor immunity.

Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain 1 – 3 . Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours. In a mouse model of glioblastoma, treatment with VEGF-C increases lymphatic drainage in the central nervous system and improves the immune response, suggesting that modulating meningeal lymphatics could enhance checkpoint inhibitor therapy.

Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

Balanced immune responses in the eyes are crucial to preserve vision. The ocular immune system has long been considered distinct, owing to the so-called ‘immune privilege’ of its component tissues. More recently, intravital imaging and transcriptomic techniques have reshaped scientific understanding of the ocular immune landscape, such as revealing the specialization of immune cell populations in the various tissues of the eye. As knowledge of the phenotypes of corneal and retinal immune cells has evolved, links to both the systemic immune system, and the central and peripheral nervous systems, have been identified. Using intravital imaging, T cells have recently been found to reside in, and actively patrol, the healthy human cornea. Disease-associated retinal microglia with links to retinal degeneration have also been identified. This Review provides an updated guide to the ocular immune system, highlighting current knowledge of the immune cells that are present in steady-state and specific diseased ocular tissues, as well as evidence for their relationship to systemic disease. In addition, we discuss emerging intravital imaging techniques that can be used to visualize immune cell morphology and dynamics in living human eyes and how these could be applied to advance understanding of the human immune system.This Review provides an overview of the immune system of the eye at steady state and in ocular disease, and it describes the links between ocular immunology and systemic disease. It highlights the intravital imaging techniques that have provided insights into immune cell morphology and dynamics in living human eyes.

Links between T cell clonotypes, as defined by T cell receptor (TCR) sequences, and phenotype, as reflected in gene expression (GEX) profiles, surface protein expression and peptide:major histocompatibility complex binding, can reveal functional relationships beyond the features shared by clonally related cells. Here we present clonotype neighbor graph analysis (CoNGA), a graph theoretic approach that identifies correlations between GEX profile and TCR sequence through statistical analysis of GEX and TCR similarity graphs. Using CoNGA, we uncovered associations between TCR sequence and GEX profiles that include a previously undescribed ‘natural lymphocyte’ population of human circulating CD8 + T cells and a set of TCR sequence determinants of differentiation in thymocytes. These examples show that CoNGA might help elucidate complex relationships between TCR sequence and T cell phenotype in large, heterogeneous, single-cell datasets. Integrating T cell sequences and gene expression profiles uncovers functional subsets in single-cell datasets.

The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients’ tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy. Tumor neoantigens versus tumor-associated antigens may have different functions in antitumor immunity depending on the strength of antigen recognition. Here the authors characterize CD8 T cell clones specific for TAA, neoantigens or viral antigens isolated from tumor and blood and show that neoantigen-specific clones have a higher structural avidity than TAA-specific ones and preferentially infiltrate tumors.