Review Articles

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.

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.

Assays for, and mechanisms of action of, neutralizing antibodies against viruses are considered here as tools to interpret and predict the activity of such antibodies in vivo, administered passively or induced by vaccination or infection.

This Review details the discovery of the interleukin-6 (IL-6) trans-signalling pathway and the subsequent development of biologics that specifically inhibit this pathway. Emerging evidence suggests that specifically targeting IL-6 trans-signalling can reduce pathological disease-promoting activities of IL-6 without blocking the protective actions of IL-6 in infection and tissue repair.

In this Review, Rotrosen and Kupper focus on the generation of tissue resident memory T cells (T_RM cells) by vaccines. They discuss our current understanding of T_RM cell generation by different vaccine platforms and explain why focusing on this population of cells is important for future vaccination strategies.

In the spleen, diverse types of fibroblastic stromal cells, as well as neuronal cells, establish a complex microanatomy that supports splenic function at homeostasis and orchestrates immune responses to infection.

Here, Ting and colleagues provide an overview of the NLR gene family, detailing the initial discovery of NLRs and the key experiments that uncovered their biology. NLRs are well known for their roles as inflammasome receptors and regulators of inflammation but they also have less appreciated roles, for example, in embryogenesis and reproduction.

Clonal haematopoiesis — the occurrence of somatic mutations and mosaic chromosomal alterations in blood cells — is associated with age-related diseases, autoimmunity, immunodeficiency and haematological neoplasms. This Review describes how myeloid and lymphoid cell dysregulation underlies this association.

Macrophages are important for host immunity to infections and for clearing waste products from tissues, but they also maintain tissue health by regulating metabolism, neuronal functions and many other biological processes. Here, Elvira Mass and co-workers discuss the different tissue-specific macrophage populations that are found throughout the body, highlighting shared and unique aspects of their developmental trajectories, transcriptional programmes and physiological functions.

Activation of the unfolded protein response during immune cell activation has emerged as making an essential contribution to the response to infection and inflammation. In this Review, the authors discuss where, how and when a disbalanced unfolded protein response can become pathological and thus a potential therapeutic target.

In this Review, Marco Colonna provides a comprehensive summary of the triggering receptor expressed on myeloid cells (TREM) family of receptors. TREMs are important for modulating signalling in myeloid cells and have now been implicated in many different disease settings, including inflammatory diseases, autoimmunity, neurodegeneration  and cancer.

Neonatal Fc receptor (FcRn) supports host defence through its role in antibody recycling and transcytosis, as well as by regulating immune effector cells together with classical Fc receptors for IgG. However, in autoantibody-mediated disease, these activities can be harmful. FcRn-blocking strategies are now showing promise in the clinic.

In addition to their well-established role in haemostasis, platelets also have an active role in the immune response. Here the authors summarize the evidence linking platelet activation to immune dysregulation and organ damage in immune-mediated inflammatory diseases, and discuss the therapeutic potential of targeting platelets.

Galectins can modulate immune cells by binding to glycosylated proteins and lipids on the cell surface, or intracellularly via carbohydrate-dependent or carbohydrate-independent interactions. This Review explores the diverse ways in which galectins affect immunity and discusses the challenges in the field.

The authors propose a new grouping of glomerulonephritis disorders based on their underlying immunopathogenesis, with a view to improving diagnosis, mechanistic understanding and treatment of these immune-mediated kidney diseases.

This Review synthesizes our current mechanistic understanding of the cellular and molecular determinants of tissue-specific antifungal host defences derived from animal models of fungal disease, humans with fungal infection-manifesting inborn errors of immunity and patients treated with fungal infection-promoting, immune-targeted biologics.