Reviews & Analysis

This Review discusses how the study of novel mouse models of human ADAR1 deficiency has led to the identification of the innate immune receptors recognizing endogenous immunostimulatory double-stranded RNA and their respective downstream signalling pathways that induce autoinflammatory pathology.

This Review covers the biology of anti-cytokine autoantibodies and their varied roles in causing, preventing and treating diseases. Recent reports of anti-type I interferon autoantibodies in critical COVID-19 have led to renewed interest in this topic, which offers fascinating insights into the reversibility of immune tolerance and the origins of autoimmunity in otherwise healthy individuals.

Cryptosporidium are protozoan parasites that infect intestinal epithelial cells and can cause severe diarrhoeal disease, particularly in malnourished children. This Review summarizes the immune mechanisms that protect against this parasitic infection, highlighting the innate mechanisms that detect Cryptosporidium at the intestinal epithelium and the adaptive immune mechanisms that mediate resistance.

This Review provides a guide to complement and its emerging roles in processes beyond innate immune defence such as in early development, tissue immunometabolism, tissue regeneration and cancer immunity. Moreover, our improved understanding of its role in disease pathology has opened new options for complement-based therapeutics.

Phagocytosis-mediated cell death — also known as ‘phagoptosis’ — regulates developmental processes, cell turnover and immunity to infections and cancer. Here, Brown summarizes the key molecular interactions involved in cell death by phagocytosis and the relevance of this process for host health.

Recent studies have revealed a family of antigen-presenting cells (APCs) marked by the transcription factor RORγt that fundamentally shape immunity, inflammation and tolerance. This article reviews heterogeneity among RORγt⁺ APCs, their associated functions and the future promise of this new field.

This Review summarizes how the processes of thymic selection together ensure that the T cell repertoire is fully functional and safe. In the thymus, T cell receptor signal strength is integrated with distinct stromal cues to result in positive or negative selection of thymocytes or the generation of regulatory cells.

Microglia are increasingly implicated in the maintenance and regeneration of myelin, which is damaged with normal ageing and in several neurodegenerative diseases. This article reviews the mechanisms by which microglia support and restore myelin health and the factors that influence these crucial microglial functions.

SARS-CoV-2 infection can lead to a diverse array of chronic symptoms, collectively termed ‘long COVID’. In this Review, Altmann and colleagues explore current thinking about the pathophysiology of long COVID and discuss potential immunological mechanisms.

This Review describes recent advances in the field of 3D in vitro modelling technologies that enable a better understanding of immune cell and tumour cell interactions in the tumour microenvironment. The authors explain how such systems can be used to assess the efficacy of novel immunotherapies, including personalized immunotherapies, for patients with cancer.

Memory B cells are critical for protection against repeated infections, particularly with viral variants, and understanding their function and development is key for successful vaccine development. This Review discusses the cellular and molecular mechanisms of memory B cell generation and reactivation and how these processes shape antibody diversity and breadth.

This article reviews growing evidence suggesting that narcolepsy, a chronic sleep disorder caused by deficiency of hypocretin (also known as orexin), has an immune-mediated basis, explores the potential role of autoreactive lymphocytes in the disease process, and proposes future research directions to elucidate its pathogenesis.

Regulatory T cells (T_reg cells) are controlled by a raft of transcription factors besides Forkhead box protein 3 (FOXP3). As detailed in this Review, these accessory transcription factors act alone or together with FOXP3 to coordinate T_reg cell specification and function, and account for heterogeneity of niche-specific T_reg cells.

Fifty years since the discovery of HMGB1 protein, its physiological and pathological roles have been extensively studied. This Review covers the structure, localization and functions of HMGB1 in immune responses, including historical foundations and recent advances.

Recent studies have highlighted the diversity and distinct nature of regulatory T cells in the intestine, where they must balance a multitude of signals from the microbiota and the diet to ensure immune homeostasis. But questions and controversies remain over their origins and regulation, as discussed here.

Here, Schenkel and Pauken consider how specific patterns of T cell trafficking and localization in tissue microenvironments shape their immune functions in acute infection and cancer settings. They further consider the relevance of this for the efficacy of immune checkpoint blockade therapy in the clinic.

Drugs that target protein kinases have had a major impact on the treatment of cancer and now are proving beneficial in numerous immunological diseases. This Review describes their clinical application, with a focus on Janus kinase inhibitors, and how they inform mechanisms of disease and have evolved to improve efficacy and safety.

In this Review, the authors consider how early-life environmental exposures shape the immune system. They highlight how diet, medicines and other environmental factors influence the establishment of the gut microbiota and can impact susceptibility to allergic disease development.

In this Perspective, Honjo and co-workers describe the discovery of PD1 and its journey to become a major target for cancer immunotherapy. It discusses the complex regulatory systems that govern PD1 expression as well as recent insights into PD1 function and the mechanisms of PD1-blocking therapies.

IgG4 has unique functional characteristics that are increasingly recognized to have a pathogenic role in autoimmunity, tumour immunology, IgG4-related diseases and anti-biologic responses, as well as a beneficial role in allergy and parasitic infections.