Reviews & Analysis

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.

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.

Koohy and co-workers discuss how we must turn to machine-learning approaches to define the antigen specificity of the many millions of possible T cell receptors. They review the models and methods currently being used to predict cognate antigens for orphan T cell receptors.