Nature Reviews Immunology - Beyond exhaustion, CD8+ T cells can adopt various dysfunctional states, including tolerant, anergic, senescent, ignorant and dying states, that compromise their ability...

Transposable elements (TEs) are mobile repetitive nucleic acid sequences that have been incorporated into the genome through spontaneous integration, accounting for almost 50% of human DNA. Even though most TEs are no longer mobile today, studies have demonstrated that they have important roles in different biological processes, such as ageing, embryonic development, and cancer. TEs influence these processes through various mechanisms, including active transposition of TEs contributing to ongoing evolution, transposon transcription generating RNA or protein, and by influencing gene regulation as enhancers. However, how TEs interact with the immune system remains a largely unexplored field. In this Perspective, we describe how TEs might influence different aspects of the immune system, such as innate immune responses, T cell activation and differentiation, and tissue adaptation. Furthermore, TEs can serve as a source of neoantigens for T cells in antitumour immunity. We suggest that TE

Messenger RNA (mRNA) vaccines are a transformative platform for inducing antigen-specific T cell and B cell responses that are now being trialled in oncology. Here we propose an immunological framework that reconciles four axes controlling the efficacy of mRNA cancer vaccines: adjuvanticity versus immunopathology, antigen immunogenicity versus tolerance, adaptive immune memory versus exhaustion, and beneficial versus maladaptive trained immunity. We argue that mRNA vaccines should be viewed as programmable constructs in which nucleoside chemistry, delivery platforms and dosing schedules can be manipulated to tune these four axes by modulating antigen identity and decay, costimulation, cytokine tone and innate stimulation. By fitting recent mechanistic and translational insights into this framework, we outline design principles for positioning mRNA cancer vaccines within an optimal window of immune activation that supports durable, tumour-specific immunity while minimizing T cell exhaus

CD8+ T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic viral infection. Here, we discuss the molecular and spatiotemporal mechanisms beyond exhaustion that underlie the inability of CD8+ T cells to eradicate malignant or chronically infected cells. We also propose a framework to enhance our understanding of these mechanisms — which include tolerization, anergy, senescence, cell death, exclusion and ignorance — with the ultimate aim of informing novel approaches to improve the clinical management of cancer and chronic viral infection. Beyond exhaustion, C

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Regulatory T (Treg) cells have a central role in the maintenance of immune surveillance and tolerance. They can migrate from lymphoid organs to blood and then into tissues and egress from tissues into draining lymph nodes. Specialized endothelial cells of blood and lymphatic vessels are the key gatekeepers for these processes. Treg cells that transmigrate across single-cell layers of endothelial cells engage in bidirectional crosstalk with these cells and regulate vascular permeability by promoting structural modifications of blood and lymphatic endothelial cells. In turn, blood and lymphatic endothelial cells can modulate Treg cell recirculation and residency. Here, we discuss recent insights into the cellular and molecular mechanisms of the crosstalk between Treg cells and endothelial cells and explore potential therapeutic strategies to target these interactions in autoimmunity, transplantation and cancer. Regulatory T (Treg) cells have an important role in the maintenance of immune

The central nervous system (CNS) has a unique relationship with the immune system, referred to as immune privilege. For many years it was thought that immune privilege was due to isolation of the CNS from the immune system, but recent findings have shown that this theory is flawed and that there is substantial neuroimmune communication, particularly at border sites that encase the CNS. These border sites include perivascular and subarachnoid spaces, the choroid plexus, the meninges and the vasculature, including the recently discovered meningeal lymphatic vessels. CNS border tissues have extensive interaction with the cerebrospinal fluid, which acts as an immune mediator, allowing the immune system at the CNS borders to respond to challenges within the CNS parenchyma. Together, CNS border tissues enable immune surveillance and protection against infections while preventing inflammatory damage to the parenchyma. A better understanding of the mechanisms of immune privilege as an accord,

Microglia, the resident immune cells of the brain, are now recognized as being active participants in the onset and progression of many neurological and neuropsychiatric disorders. As a result, substantial effort has been made in finding ways to target, deplete or modulate the aberrant phenotypes of the microglia that are present in these different disease states, albeit with varied levels of success. The gut microbiota has recently emerged as a master regulator of microglia throughout the lifespan; here, we propose that this microbiota–microglia cross-talk may have major implications for our understanding of neurological disorders and neuropsychiatric diseases. We focus on the latest advances in understanding gut–microglia communication in the context of microglial heterogeneity and microglia-related functions, as well as considering the evidence for effects of these pathways on diseases and disorders of the central nervous system. We also address the challenges, opportunities and cli

Centenarians — individuals aged 100 years or older — constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105–109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotyp

Cytotoxic lymphocytes counter intracellular pathogens and cancer by recognizing and destroying infected or transformed target cells. The basis for their function is the cytolytic immune synapse, a structurally stereotyped cell–cell interface through which lymphocytes deliver toxic proteins to target cells. The immune synapse is a highly dynamic contact capable of exerting nanonewton-scale forces against the target cell. In recent years, it has become clear that the interplay between these forces and the biophysical properties of the target influences the entirety of the cytotoxic response, from the initial activation of cytotoxic lymphocytes to the release of dying target cells. As a result, cellular cytotoxicity has become an exemplar of the ways in which biomechanics can regulate immune cell activation and effector function. This Review covers recent progress in this area, which has prompted a reconsideration of target cell killing from a more mechanobiological perspective. Cytotoxic

Alterations in key metabolic pathways are required for tumour development and the adaptation of tumour cells to intrinsic or extrinsic stresses, as well as for the regulation of immune cell fate and immune responses in the tumour microenvironment. In particular, the dysregulation or alteration of certain metabolites produced by tumour cells has been shown to be important in creating the immunosuppressive tumour microenvironment. Recent studies have broadened our understanding of the interactions between metabolites and antitumour immunity. Here we highlight how, beyond their metabolic role, metabolites can function as signalling molecules to modulate the behaviours of immune cells and tumour cells. We also discuss potential therapeutic strategies targeting specific metabolites and future research directions in metabolite sensing. Certain metabolites in the tumour microenvironment signal between tumour cells and infiltrating immune cells. Here, the authors discuss how metabolites as sig

Cancer immunotherapies have shown promise and success in a number of different types of tumours, yet many solid epithelial tumours remain recalcitrant. Somatic mutations in tumour cells can lead to the expression of neoantigens, which are potent targets of the human antitumour immune response. These can be targeted through adoptive cell transfer (ACT) of neoantigen-specific T cells, including tumour-infiltrating lymphocytes (TILs) or T cell receptor (TCR)-engineered T cells (TCR-T cells), an approach that has been shown to achieve tumour regression in patients with different types of metastatic solid tumours including melanoma, breast and gastrointestinal cancer. Immunogenomics, systems immunology and genome editing now provide multidisciplinary tools to design cell therapies against solid cancer. Here, we review historical efforts and our current conceptual understanding of ACT using TILs or TCR-T cells. Moreover, we highlight emerging correlates of response to ACT and novel strategie

Kidney diseases are widespread and represent a considerable medical, social and economic burden. However, there has been marked progress in understanding the immunological aspects of kidney disease. This includes the identification of distinct intrarenal immunological niches and characterization of kidney disease endotypes according to the underlying molecular immunopathology, as well as a better understanding of the pathological roles for T cells, mononuclear phagocytes and B cells and the renal elements they target. These insights have improved the diagnosis of kidney disease. Here, we discuss new developments in our understanding of kidney immunology, focusing on immune mechanisms of disease and their translational implications for the diagnosis and treatment of kidney disease. We also describe the immune-mediated crosstalk between the kidney and other organs that influences kidney disease and extrarenal inflammation. Kidney diseases affect millions globally. Advances in understandi

Nature Reviews Immunology - Macrophages are innate immune sentinels providing frontline defence against infection. This Review describes the inducible mechanisms used by macrophages to kill...

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The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harbours diverse non-parenchymal cell populations, including immune cells. Among these, Kupffer cells, the resident macrophages of the liver, are critical modulators of liver function and immunity. Emerging research highlights their dynamic roles throughout life, from maintaining tissue homeostasis to shaping the balance between immune tolerance and activation in adulthood. Kupffer cells are located in liver sinusoids, where they act as frontline defenders, clearing pathogens and cellular debris from the circulation. Beyond their established phagocytic and immune regulatory functions, Kupffer cells influence metabolic processes, tissue repair and oncogenesis. Moreover, they shape the response of the liver to metabolic disorders such as metabolic dysfunction-associated steat

The cell-autonomous innate immune system is responsible for sensing and mitigating viral infection at the level of individual cells. Many of the mechanisms used by the cell-autonomous innate immune system in eukaryotic cells are ancient and have evolutionary roots in bacterial systems that defend against phage infection. Studies from recent years have shown that modification of the free nucleotide pool is central to many of these conserved immune mechanisms. In this Review, we explain how immune pathways manipulate the available pool of nucleotides to deprive viruses of molecules essential for their replication, how immune proteins chemically modify nucleotides to generate immune signalling molecules, and how cell-autonomous innate immune mechanisms produce altered nucleotides that poison viral replication. We also discuss the mechanisms used by viruses to antagonize nucleotide-based immunity. Finally, we explore the evolutionary logic of using nucleotides as building blocks for immune

Food allergy is an acute IgE-mediated reaction that occurs in response to food components and affects 1–10% of the global population. It is often thought to be a disease of the gastrointestinal tract, in which oral exposure to a food allergen induces an IgE-sensitizing response that primes the host immune system to react to the eliciting allergen following subsequent oral exposure. However, emerging evidence from clinical and basic research studies suggests that maladaptive immune responses in the skin also contribute to the development of food allergy. These responses can promote the development of food-specific IgE and reshape the gut immune microenvironment in a manner that predisposes to IgE-mediated activation of mast cells and clinical manifestations of allergic disease following subsequent food exposures. In this Review, we discuss how different routes of exposure to food antigens can contribute to allergic sensitization and describe how mast cells ultimately drive the allergic

Cytokines are essential mediators of immune functions and regulate many other biological processes, ranging from fetal development to ageing. Dysregulation of cytokine responses can substantially increase the risk of disease and so their activity requires tight control. The formation of cytokine homodimers, heterodimers and multimers has evolved as a versatile mechanism to regulate cytokine biology, in which multimerization can enable or attenuate their activity, diversify signalling outcomes and drive signalling bias. Here, we discuss the structure–function implications of cytokine multimerization for type I cytokines (for example, the IL-6 and IL-12 cytokine families), type II cytokines (for example, the IL-10 and interferon families), cytokines that signal through immunoglobulin-family receptors (for example, the IL-1 and M-CSF families) and also for the IL-17, TNF and TGFβ cytokine families. We highlight the influence of multimerization on cytokine activity and receptor engage

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Current therapies for relapsing MS primarily target the peripheral immune system but have consistently failed to address mechanisms underlying disease progression, which are thought to involve CNS-resident glial cells such as astrocytes, microglia and oligodendrocytes. Recent technological advances have revealed the functional heterogeneity of these glial cells, highlighting their crucial roles in inflammation, demyelination, remyelination and neurodegeneration. In this Review, we summarize emerging insights into the diversity, function and regulation of glial cells in MS and inflammation in general, highlight their interactions with immune cells and non-immune cells in the CNS, and discuss potential strategies for their therapeutic modulation. A growing appreciation of the diversity of glial cells, including astrocytes, microglia and oligodendrocytes, is providing new insights into their rol

JAK inhibitors target a large group of cytokines that signal through the JAK–STAT pathway and are typically used clinically as immunosuppressive agents. However, recent work has demonstrated the paradoxical ability of JAK inhibitors to enhance antitumour and antiviral immune responses and established their synergy with immune checkpoint inhibitors in early-stage clinical trials. In this Perspective, we consider why JAK inhibitors, which are typically used as immunosuppressive drugs, can have immune-enhancing effects, exploring the potential mechanistic basis and the opportunities to harness this effect to improve cancer immunotherapy. JAK inhibitors are typically used to suppress the immune system but have also been shown to enhance antitumour and antiviral immune responses. In this Perspective, Zak and Teijaro explore the basis of the immune-enhancing properties of JAK inhibitors and consider whether we can exploit these properties for cancer therapy.

Post-translational protein modifications by the small ubiquitin-like modifier (SUMO) family have been shown to regulate immune cells in the context of infection, autoimmunity and, more recently, cancer. Recent clinical trials investigating sumoylation inhibition as a therapeutic approach for cancer have established that sumoylation has important immune modulatory effects. Sumoylation suppresses transcription factors in innate immune cells and in cytotoxic T cells through the direct modification of these factors, which leads to the recruitment of transcriptional repressor complexes containing histone deacetylases. By contrast, in regulatory T cells and T helper 17 cells, sumoylation of transcription factors can enhance transcriptional activity by recruiting transcriptional coactivators. Sumoylation is also involved in the repression of IFNB1 and endogenous retroviruses and is therefore important for regulating interferon expression. A central theme from literature is that the sumoylatio

Over recent years, immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various solid neoplasms, including melanoma and lung carcinoma. A proportion of these malignancies exhibit a baseline immunological configuration that can be successfully targeted with ICIs to support durable clinical responses. Conversely, breast neoplasms other than the triple-negative subset respond poorly to ICIs, reflecting numerous tumour-intrinsic and microenvironmental barriers against effective anticancer immunity. Notably, most hormone receptor-positive breast cancers tend to have limited immunogenicity and to establish a local and systemic immunosuppressive microenvironment that hinders responses to ICIs. Here, we summarize the main immunological features of human breast tumours, whenever possible comparing across disease subtypes, stages and treatment outcomes. Understanding the complex interplay between breast cancer, its hormonal regulation and the immun