Immunology

Lymph nodes are secondary lymphoid organs in which immune responses of the adaptive immune system are initiated and regulated. Distributed throughout the body and embedded in the lymphatic system, local lymph nodes are continuously informed about the state of the organs owing to a constant drainage of lymph. The tissue-derived lymph carries products of cell metabolism, proteins, carbohydrates, lipids, pathogens and circulating immune cells. Notably, there is a growing body of evidence that individual lymph nodes differ from each other in their capacity to generate immune responses. Here, we review the structure and function of the lymphatic system and then focus on the factors that lead to functional heterogeneity among different lymph nodes. We will discuss how lymph node heterogeneity impacts on cellular and humoral immune responses and the implications for vaccination, tumour development and tumour control by immunotherapy. This Review from Wolfgang Kastenmüller and colleagues highlights the heterogeneity that exists among lymph nodes at different anatomical locations. The authors consider the factors that contribute to lymph node heterogeneity and explain the relevance of this for the immune response, particularly in the contexts of vaccination and cancer.

The year 2023 has witnessed the Journal of Experimental Medicine (JEM)'s unwavering commitment to publishing groundbreaking studies that advance our understanding of all aspects of disease pathogenesis and therapeutic approaches.
As we reflect at the end of 2023, we are delighted to present the annual Best of JEM series—a compilation that spotlights cutting-edge research spanning immunology, host-pathogen interactions, cancer biology, tumor immunology, vascular biology, neuroscience, and other pivotal domains.
We extend our heartfelt gratitude to the authors, reviewers, and readers who have been instrumental in shaping the impactful narrative of JEM. Thank you for being an integral part of our scientific community. We hope that this collection will serve as a source of inspiration and insight.

Through single-cell transcriptomic analysis, Feng et al. identified a novel T follicular helper cell subset with stem cell–like transcriptional features and lon

Abstract. On T cell activation, upregulation of gene expression produces the protein required for the differentiation and proliferation of effector cell populat

Series Editors: Jo Spencer, Mats Bemark and Thomas J Tull

Over 50 years on from the discovery of their role as the source of antibodies, B cells remain one of

Natural killer (NK) cells are innate lymphoid cells (ILCs) that serve as a first line of defense against pathogens and tumors. Historically, their classification hinged on a limited array of surface protein markers. However, recent advancements in single-cell technologies, such as single-cel

Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases. Cell death can result from the activation of dedicated programmed cell death machineries or disruption of pro-survival mechanisms. This Review describes the different major mechanisms of cell death and discusses recent insights into their relevance to disease.

A History Timeline About Immunology. Immunology, the study of the immune system and its responses to invading pathogens, has a rich an

Cytokines mediate cell–cell communication in the immune system and represent important therapeutic targets1–3. A myriad of studies have highlighted their central role in immune function4–13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine–cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1β induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell–cell communication networks in any immune response. An extensive global transcriptomics analysis of in vivo responses to 86 cytokines across more than 17 immune cell types reveals enormous complexity of cellular responses to cytokines, providing the basis of the Immune Dictionary and its companion software Immune Response Enrichment Analysis.

In addition to the known ACE2 receptor, the SARS-CoV-2 virus can also bind to the RAGE receptor found in white blood cells.

Skin-resident CD8+ T cells include distinct interferon-γ–producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)–producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet–Hobit–IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS–c-Maf–IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.