Reviews & Analysis

This Perspective discusses current knowledge of the diverse roles played by different macrophage populations within the Mycobacterium tuberculosis-infected lung. The underlying hypothesis is that disease outcome depends on macrophage ontogeny and epigenetic programming, in addition to the immune environment.

This Review summarizes mechanisms for the regulation of cGAS–STING signalling, describes its crosstalk with other signalling pathways, and outlines the diverse cellular outcomes of cGAS–STING biology and its roles in inflammatory disease, ageing and tumorigenesis.

This Review discusses recent advances in our understanding of the biology of endogenous tissue regeneration in the thymus, highlighting the clinical implications of poor thymic recovery.

Here the authors describe the different ways that cancer cells evade the immune system and how these mechanisms impact immunoediting and tumour clonality. They suggest that in tumours that become highly heterogeneous, presentation of subclonal antigens can result in immune evasion and may explain their poor prognosis and response to immunotherapy.

This Review provides an in-depth examination of how inflammation contributes to neurodegeneration in Alzheimer disease. The authors explore the impact of extrinsic factors, such as brain trauma, diet and infections, and host-intrinsic factors, such as the activity of microglial cells and other immune, vascular and neuronal cell populations, on disease development. They also highlight emerging drugs that target this inflammatory component for therapy of Alzheimer disease.

There is emerging evidence that mice with a history of microbial exposures can better model the human immune system than laboratory mice maintained in pathogen-free conditions. In this Perspective, Rehermann and colleagues summarize different approaches that have been used to incorporate microbiota and pathogen exposures into laboratory mouse models. They suggest that the term ‘mice with natural microbiota’ should be used instead of ‘dirty mice’ to describe these systems in the future.

The oral mucosa is a critical barrier tissue that is continually exposed to pathogens, but antiviral immune responses in this tissue are poorly understood. Moreover, recent viral outbreaks, including SARS-CoV-2 and mpox, feature oral symptoms. This Review discusses antiviral immunity in the oral cavity and presents current mouse models for the study of oral viral infections.

The basic-residue-rich sequence (BRS) is a common motif located in the cytoplasmic tail of most immunoreceptors. This Perspective highlights the mechanisms of BRS signalling, its pathophysiological importance and how to harness BRS signalling to develop next-generation immunotherapy.

Thirty years ago, Polly Matzinger introduced the ‘danger theory of immunity’, which proposed that danger and damage have a decisive role in immune responses. In this Perspective, Kroemer et al. reflect on the impact of the danger theory, discuss its molecular foundations and present an extended version of it. They propose that immunological self-tolerance is organized in a hierarchy that functions in a close-to-fail-safe cascade-like fashion, thereby reconciling Matzinger’s danger theory with the self–non-self-discrimination hypothesis.

This Review discusses how adipose tissue can regulate host immune function via the release of adipokines, including adiponectin, leptin and various cytokines. These adipokines contribute to immune responses and metabolic inflammation and can have both beneficial and detrimental effects on host physiology. In obesity, adipokine release can promote insulin resistance and cardiovascular diseases; as such, there is interest in targeting these mediators for therapy of various metabolic disorders.

Single-cell multi-omic profiling has revealed how the immune system is established in the human embryo, mapping in unprecedented detail the emergence of progenitors, the handover of haematopoiesis between sites and the diversification of cell lineages across the body.

CAR T cells have transformed the treatment of some haematological cancers. This Perspective explores how insights into T cell receptor signalling have enabled the engineering of CAR formats that can outcompete currently approved CARs in preclinical models and clinical trials.

This Perspective considers present and historical paradigms of therapeutic cancer vaccines and describes a conceptual framework, termed Vax-Innate, to simultaneously generate robust tumour-specific T cell responses and remodel the suppressive tumour microenvironment (TME). The authors detail how this strategy could be achieved through systemic vaccination and by using immune modulators to improve dendritic cell and macrophage function in the TME.

This Review provides an overview of arginine and arginase function in immune cells, at the steady state and during disease. It considers the relevance of this pathway for metabolic, immune and genetic regulation, together with possible therapeutic interventions.

The aryl hydrocarbon receptor (AHR) can sense and initiate immune responses to many different infectious organisms. Here, Moura-Alves and colleagues review the role of the AHR in host–pathogen interactions and explore the therapeutic potential of targeting the AHR in the context of different infectious diseases.

Oxygen levels vary throughout the body and immune cells must adapt to these changes, both during homeostasis and in disease. Here, the authors discuss the impact of physiological subatmospheric oxygen levels (physioxia) as well as disease-related hypoxia on immune cell responses. They consider the therapeutic relevance of understanding how oxygenation affects immune responses in various diseases, including tuberculosis, COVID-19 and cancer.

Macrophages are associated with many human diseases but are challenging to study in vivo. Here, Ginhoux and colleagues discuss how iMacs — macrophages generated from induced pluripotent stem (iPS) cells — can enable disease modelling, including through the use of patient-derived iPS cells and 3D organoid co-culture systems. Ultimately, these iMac-based approaches can improve our understanding of macrophage biology in both health and disease.

Technological advances in cellular and molecular immunology are providing unprecedented new insights into evolutionary immunology. This Perspective highlights new insights into the immune systems of different vertebrate species and discusses emerging general principles of immune system function.

Macrophages are innate immune sentinels providing frontline defence against infection. This Review describes the inducible mechanisms used by macrophages to kill bacterial pathogens and/or inhibit their growth and outlines how this knowledge might be exploited in the design of host-directed therapies.

For effective central T cell tolerance, developing thymocytes must encounter a diverse range of self-antigens presented by various thymic cells. Here, the authors describe how medullary thymic epithelial cells, dendritic cells and B cells are uniquely adapted through promiscuous gene expression, strategic positioning and inflammatory signals, which shape the peptide–MHC ligandomes and extend self-antigen visibility in the thymic microenvironment.