Peripheral sensory neurons, long appreciated for their role in detecting environmental stimuli, also play an active role in local and systemic immune responses. In response to tissue damage, the coordinated activation of peripheral sensory neurons and immune cells facilitates tissue repair. When dysregulated, however, these neuroimmune interactions can become maladaptive and contribute to chronic disorders such as chronic pain or headache. Recent single-cell transcriptomic studies have uncovered multiple distinct sensory neuron subtypes, each with unique molecular profiles, anatomical niches, and immune functions. In this review, we examine how distinct sensory neuron subtypes coordinate immune responses in barrier and internal tissues, forming cell type- and context-specific neuroimmune circuits. We also discuss how disruption of these circuits contributes to neuroinflammatory diseases such as atopic dermatitis and neuropathic pain. Clarifying these subtype-specific neuroimmune mechanisms offers a path toward more precise and effective therapies that target maladaptive neuroimmune circuitry in multiple disorders.

The intensity of T cell receptor (TCR) signaling controls thymic positive and negative selection of conventional T cells (Tconv cells) and regulatory T cells (Treg cells), as well as their peripheral activation. Accordingly, the effects of graded TCR signal reduction manifest as a disease spectrum encompassing T cell immune deficiency, latent autoimmunity, and overt autoimmune disease. TCR signal attenuation to a certain range-for example, through hypomorphic mutation of the ZAP-70 (ζ chain-associated protein-70) molecule or reduced expression of its normal form-shifts the TCR repertoire of Tconv and Treg cells toward higher self-reactivity and hampers Treg cell generation. These alterations together lead to spontaneous development of various T cell-mediated autoimmune and inflammatory diseases. Additional host genetic and environmental factors exert secondary effects on disease phenotype and manifestation. In addition, pharmacological attenuation of TCR signaling to a certain range in peripheral T cells can selectively reduce mature Treg cells and evoke effective antitumor immune responses. Collectively, TCR-proximal signaling is a key target for controlling autoimmunity and cancer immunity.

The persistence of SARS-CoV-2 infections at a global level reflects the repeated emergence of variant strains encoding unique constellations of mutations. These variants have been generated principally because of a dynamic host immune landscape, the countermeasures deployed to combat disease, and selection for enhanced infection of the upper airway and respiratory transmission. The resulting viral diversity creates a challenge for vaccination efforts to maintain efficacy, especially regarding humoral aspects of protection. Here, we review our understanding of how SARS-CoV-2 has evolved during the pandemic, the immune mechanisms that confer protection, and the impact viral evolution has had on transmissibility and adaptive immunity elicited by natural infection and/or vaccination. Evidence suggests that SARS-CoV-2 evolution initially selected variants with increased transmissibility but currently is driven by immune escape. The virus likely will continue to drift to maintain fitness until countermeasures capable of disrupting transmission cycles become widely available.

The mammalian gut is a vast, diverse, and dynamic single-layer epithelial surface exposed to trillions of microbes, microbial products, and the diet. Underlying this epithelium lies the largest collection of immune cells in the body; these cells encounter luminal substances to generate antigen-specific immune responses characterized by tolerance at homeostasis and inflammation during enteric infections. How the outcomes of antigen-specific tolerance and inflammation are appropriately balanced is a central question in mucosal immunology. Furthermore, how substances large enough to generate antigen-specific responses cross the epithelium and encounter the immune system in homeostasis and during inflammation remains largely unexplored. Here we discuss the challenges presented to the gut immune system, the identified pathways by which luminal substances cross the epithelium, and insights suggesting that the pathways used by substances to cross the epithelium affect the ensuing immune response.

The immune system, critical for human health and implicated in many diseases, defends against pathogens, monitors physiological stress, and maintains tissue and organismal homeostasis. It exhibits substantial variability both within and across individuals and populations. Recent technological and conceptual progress in systems human immunology has provided predictive insights that link personal immune states to intervention responses and disease susceptibilities. Artificial intelligence (AI), particularly machine learning (ML), has emerged as a powerful tool for analyzing complex immune data sets, revealing hidden patterns across biological scales, and enabling predictive models for individualistic immune responses and potentially personalized interventions. This review highlights recent advances in deciphering human immune variation and predicting outcomes, particularly through the concepts of immune setpoint, immune health, and use of the immune system as a window for measuring health. We also provide a brief history of AI; review ML modeling approaches, including their applications in systems human immunology; and explore the potential of AI to develop predictive models and personal immune state embeddings to detect early signs of disease, forecast responses to interventions, and guide personalized health strategies.

The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype–phenotype correlations and the spectrum of Aire-associated autoimmunity—including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.

Gastrointestinal nematode (GIN) infection has applied significant evolutionary pressure to the mammalian immune system and remains a global economic and human health burden. Upon infection, type 2 immune sentinels activate a common antihelminth response that mobilizes and remodels the intestinal tissue for effector function; however, there is growing appreciation of the impact GIN infection also has on the distal tissue immune state. Indeed, this effect is observed even in tissues through which GINs never transit. This review highlights how GIN infection modulates systemic immunity through (a) induction of host resistance and tolerance responses, (b) secretion of immunomodulatory products, and (c) interaction with the intestinal microbiome. It also discusses the direct consequences that changes to distal tissue immunity can have for concurrent and subsequent infection, chronic noncommunicable diseases, and vaccination efficacy.

The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer.

Elite controllers are a heterogeneous group of people living with HIV who control viral replication without antiretroviral therapy. There is substantial evidence that at least some elite controllers are infected with replication-competent virus, thus they may serve as a model of a functional cure of HIV. The mechanisms responsible for virologic control have been actively studied. The most objective data support CD8+ T cell-based mechanisms of control, but other immune responses, mediated by antibodies and natural killer cells, may also play a role in controlling viral replication. In this article, we review the evidence for different mechanisms of immune control in these remarkable individuals.

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1β and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, the active NLRP3-NEK7 (NIMA-related kinase 7)-ASC inflammasome disk, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome.