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.
Glycan-binding proteins (GBPs), including Galectins, sialic acid–binding immunoglobin-type lectins (Siglecs), and C-type lectin receptors (CLRs), are key regulators of immune cell development, activation, differentiation, trafficking, and homeostasis. By interpreting glycan-encoded information, these lectins shape immune responses across T, B, and myeloid cell lineages. Galectins, primarily soluble β-galactoside-binding proteins, function through both extracellular and intracellular mechanisms. Siglecs, expressed on various immune cells, recognize sialoglycans and initiate immunoregulatory signaling, while CLRs detect diverse glycans on pathogens and host cells and thereby contribute to immune sensing and modulation. These glycosylation-dependent pathways serve as integrative hubs that couple intrinsic immune programs with environmental and intracellular cues. In this review, we discuss cellular mechanisms by which GBPs govern immune cell fate under homeostatic physiologic conditions, and we emphasize both conserved and context-dependent roles. Moreover, we address how glycan–GBP dysregulation contributes to immune dysfunction and pathology and how targeting these endogenous glycoimmune checkpoints may open new avenues for immunotherapy.
Affinity for antigen is a fundamental parameter of humoral immunity. It determines the B cell clones that participate in the response, it is a readout of clonal selection as the response progresses, and the magnitude of its improvement in T cell-dependent responses is a major criterion of success. But another important attribute of immunity at initiation, propagation, and cessation is the diversity of antigen binding by B cells and antibodies. As such, the diversity of antigen receptors is important at the outset of the response in providing a broad population from which B cell fates can be selected. Equally, within the germinal center, specific mechanisms operate to diversify the B cell population for affinity-based selection, which itself promotes clonal restriction to achieve its goals. However, the importance of sustaining diversity of antigen recognition at all stages of the response, not only in the composition of the B cell memory compartments, is often lost by the focus on affinity as the key measure of immunity. In this article, we consider recent developments in understanding B cell selection into, persistence within, and exit from T cell-dependent immune responses and how these processes are calibrated to ensure diversity of antigen recognition persists into memory in spite of the clonal narrowing that is the usual outcome of affinity-driven selection.
Here we introduce the Cross-Organ Neuroimmunology of Behavior (CONB) Network, a framework that reconceptualizes behavior as an emergent property of a distributed, whole-body immune-brain network. It builds on knowledge of neuroimmune communication, including cytokine modulation of neural activity and synaptic plasticity, neuroglial-immune interactions, and neuroendocrine pathways, forming a shared language for cross-organ signaling. We examine how peripheral organs function as network nodes, translating local immune or physiological changes into systemic signals that influence brain circuits and behavior. Integrating these axes reveals emergent network properties, such as redundant pathways (degeneracy) that enhance resilience and hub organs that exert disproportionate influence on network stability. This model links complex behavior to multisystem disease cross talk, reframing brain diseases as systemic network dysregulation. Ultimately, the CONB Network perspective informs precision medicine by leveraging immune biomarkers to identify patient subtypes and guide therapeutic strategies to recalibrate cross-organ neuroimmune networks and restore system-wide homeostasis.
The major effector cells of antitumor immunity are killer lymphocytes that recognize and eliminate tumor cells. The fact that tumor cells look a lot like normal cells poses a challenge to antitumor immune control. A danger signal from the tumor or from antigen-presenting cells that have taken up dying tumor cells is needed to distinguish tumor cells from normal cells to fully activate killer cell effector functionality and memory and thereby control the tumor. How a tumor cell dies strongly affects whether the immune system sees it as dangerous. Activation of innate immunity in the tumor, including interferon signaling and necrotic cell death (e.g., necroptosis and pyroptosis), sounds a potent immune alarm. Pyroptosis plays an important role in tumor immunity by generating an inflamed tumor microenvironment. However, it is a double-edged sword that can both promote tumorigenesis and increase the effectiveness and cytotoxicity of cancer therapy. In this article, we review what is known about the role of tumor cell pyroptosis, which is arguably the most inflammatory type of cell death, in antitumor immunity and discuss whether it could be safely harnessed to broaden the range of tumors that respond to immunotherapy.
Immune inhibitory receptors are negative regulators of immune cells and, as such, dampen immune responses. Blocking inhibitory receptors in cancer results in not only powerful antitumor responses but also a diverse array of immune-related adverse events, reminiscent of inflammatory disease. These effects of blocking inhibitory receptors emphasize their importance in maintaining immune balance. Recent efforts therefore aim to therapeutically activate inhibitory immune receptors for the treatment of inflammatory conditions. To design effective ways to ligate inhibitory receptors and selectively induce inhibitory signaling in vivo, we must thoroughly grasp their mode of action. In this article, we review current understanding of the molecular mechanisms by which inhibitory immune receptors dampen inflammation. We particularly focus on ligand recognition and intracellular signaling and examine the state of the art of inhibitory receptor targeting in the clinic. Finally, we lay out the unknowns that must be addressed for the best therapeutic strategy to reap the benefits and mitigate potential risks of targeting inhibitory immune receptors in inflammatory diseases.
The exploration of neuroimmune interactions at tissue barriers has become pivotal for our understanding of how organisms survive and adapt to challenging environments. Serving both as a physical barrier and a sensory organ, the skin has evolved as a key interface where sensation and immunity dynamically converge. In this review, we first explore the microanatomy of the skin neuroimmune system. We then discuss current knowledge on the local regulation of skin immunity by sensory neurons in steady state, injury, and infection. We highlight key pathways involved in resistance to environmental insults and discuss how their dysregulation contributes to skin physiopathology. Our emphasis on the afferent neuronal wiring connecting the skin and the brain is followed by a detailed examination of the spinal and brain efferent pathways, including neuroendocrine and cognitive circuits, that remotely modulate skin immunity. By integrating cutting-edge insights from neurobiology, immunology, and skin biology, we present a holistic view of how the nervous system sustains homeostasis of the cutaneous barrier.
FOXP3 + regulatory T cells (Tregs) have well-defined roles in limiting systemic immune responses against diverse stimuli. However, the observation that a subset of Tregs also enter nonlymphoid tissues, where they assume additional functions, has become increasingly apparent. These tissue-resident Tregs have diverse beneficial roles in tissue physiology, such as aiding homeostasis and promoting tissue repair and regeneration. In this article, we survey the state of knowledge of tissue Treg form and function in fat, muscle, heart, brain, skin, lung, and gut tissue. From a synthesis of the broader scope of the molecular features and cellular kinetics emerges a converging program of tissue residency shared across tissues and species. A core residency module drives tissue residency for Tregs, with a dynamic cellular flux of tissue-resident cells during homeostasis and disease. Finally, we review the potential for clinical translation and the key unknowns to address for the therapeutic exploitation of this enigmatic population.
Focusing on adipose tissue function, this review examines the neuroimmune mechanisms by which sympathetic neurons regulate body weight. Under healthy conditions, anti-inflammatory cues from perineurial barrier cells, mesenchymal cells, and immune cells support sympathetic-adipose communication, in part through the release of neurotrophic factors that sustain local neuronal production of fat-reducing neurotransmitters and neuropeptides such as noradrenaline and neuropeptide Y. In obesity, chronic hyperleptinemia leads to progressive weakening of the sympathetic peri-neurial barrier, thereby triggering neuroinflammation and sympathetic neuropathy. These effects disrupt local sympathetic signaling to adipose tissue and exacerbate weight gain. Notably, sympathetic neuronal release of neuropeptide Y and tachykinins is essential for brown adipose tissue thermogenesis. Finally, we critically examine shared neuroimmune and immunometabolic mechanisms in obesity and cancer, and we propose that impaired neuroimmunometabolic signaling may contribute to the well-established epidemiological link between these diseases.
C-type lectin receptors (CLRs) present on myeloid cells provide crucial signals for the induction of innate and adaptive immune responses. Their broad ligand specificity places them in a perfect position to sense both microbial intruders and signs of tissue injury or cell death. In this article, we review the mechanisms that link CLR engagement to tailored cellular responses against those perceived threats. We discuss not only how molecular interplay between signaling by CLRs and by other pattern recognition receptors fine-tunes host-protective responses but also how these receptors can lead to pathological immune responses. An understanding of how these responses are regulated may offer strategies for treating not just infectious diseases but also autoimmune or malignant disorders.
Type III interferons are essential immune mediators playing pleiotropic roles during health and disease. In this review, we highlight the molecular and cellular pathways that lead to the production of type III interferons. We also describe their exquisite capacity to act at primary barrier tissues such as those in the intestine, airways, urogenital tract, and skin, as well as to act in other organs such as the liver and thymus. We characterize the activity of type III interferons on distinct cell types in different tissues and organs and detail their impact for the host in the context of viral, bacterial, helminth, and fungal infections. Additionally, we illustrate roles of type III interferons during the development of inflammatory diseases such as inflammatory bowel disease, acute respiratory distress syndrome, asthma, solid tumors, and lupus. Overall, we summarize the dichotomous roles played by this class of interferons and highlight the knowledge gaps that must be addressed to harness type III interferons against multiple human diseases.
The central role of CD8+ T cells in HIV clearance makes them key targets in vaccine and cure strategies. This review examines our evolving understanding of CD8+ T cell-mediated HIV control and its application to curative and preventative interventions. We discuss how CD8+ T cell stemness contributes to protection along the TCF-1 (T cell factor 1) and TOX (thymocyte selection-associated high-mobility group box) axis. We highlight emerging insights, informed by novel clinical trial frameworks, into CD8+ T cell dynamics during acute HIV infection, early therapy, and treatment interruption. Furthermore, we discuss the spatial heterogeneity of CD8+ T cell function in lymphoid tissues, which underscores the antiviral potential of CD8+ T cells during chronic infections and the structural and immunological constraints that limit the clearance of HIV within follicular niches. Looking ahead, we highlight a newly developed cytomegalovirus-vectored vaccine design targeting HLA-E-restricted CD8+ T cells within the broader context of HLA-E biology, along with advances in HIV chimeric antigen receptor-T cell therapy and HIV-specific T cell receptor engineering.
Acting alongside MHC proteins, which present peptide antigens, the CD1 system displays lipid antigens to T cells. Recent studies have defined two general mechanisms of T cell receptor (TCR) binding to human CD1a, CD1b, CD1c, and CD1d proteins. The classical mechanism involves TCR corecognition of lipid antigens and CD1 proteins. In the second mechanism, however, other αβ and γδ TCRs directly recognize the surface of CD1 in a lipid-independent manner, which partially bypasses the need to identify lipid autoantigens in disease states. In this article, we review the development of new experimental tools such as cell-wide lipidomic investigation of self-lipids, endogenously loaded CD1 tetramers, and human CD1 transgenic mice. These tools are revealing nonredundant roles for CD1 in immune response and are providing evidence that CD1-reactive T cells participate in disease lesions in human skin and gut. Further, the unexpected discovery of lipid blockers of CD1-TCR interaction supports new approaches to immunomodulation.
A wide variety of suppressive pathways have been investigated in efforts to understand the basis for immune tolerance. Although the contribution of CD4+ regulatory T cells (Tregs) to self-tolerance has been extensively studied, less attention has been given to CD8+ Tregs. Here we review recent insights into the development, function, and potential clinical applications of this regulatory subset. We focus on CD8+ Tregs that recognize self-peptides associated with MHC-Ib products and that express Ly49/KIR (killer cell immunoglobulin-like receptor) coinhibitory receptors. Recent analyses of their T cell receptor repertoire, thymic differentiation, and mechanism of suppression are summarized. Identification of the human homolog of these cells has suggested new strategies for CD8+ Treg-dependent immunotherapy for autoimmune disease and cancers.
Humans are metaorganisms, composed of both host (human) cells and a roughly equal number of commensal microorganisms—collectively known as the microbiome—residing primarily at epithelial barrier surfaces. This review considers human cancer as a disease of the metaorganism, to which the microbiome contributes by influencing genome stability, tissue organization, inflammation, immunity, tumor initiation and promotion, metastasis formation, and therapeutic response. We summarize evidence demonstrating that machine learning models trained on patients’ microbiome features moderately predict clinical response to immunotherapy and the development of immune-related adverse events. We review results from single-arm and randomized clinical trials wherein fecal microbiome transplantation from therapy-responsive patients or healthy donors, when combined with therapy targeting programmed cell death 1 (PD-1), improved outcomes in PD-1-refractory patients or served as an effective first-line intervention. We conclude by highlighting the emerging opportunities and ongoing challenges in leveraging the microbiome to enhance the efficacy and safety of cancer immunotherapy.
“I appeared as a dewdrop, and disappearing as it is. All of my beloved Naniwa (Osaka) is just a dream of dreams.” This quote is the funeral ode of Hideyoshi Toyotomi, who is regarded as a “Great Unifier of Japan” for his role before the Tokugawa Shogunate. Even though he was born into an extremely poor farming family, Toyotomi rose to the top nonhereditary position in the emperorship, called the kanpaku , or chief advisor to the emperor, at the end of the sixteenth century. I personally do not like the man because of the bloody dictatorships he represents, but this ode touches my heart; he must have felt empty at the end of his life. This ode also reminds me of “The Myth of Sisyphus,” written by Albert Camus, in which Sisyphus must repeatedly roll a big stone to the top of a mountain as a punishment from the gods. Camus writes, “The struggle itself towards the heights is enough to fill a man's heart.” That said, I will write about my life as a continuously struggling molecular biologist and immunologist.
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.
CD8 T cells play a critical role in antitumor immunity. However, over time, they often become dysfunctional or exhausted and ultimately fail to control tumor growth. To effectively harness CD8 T cells for cancer immunotherapy, a detailed understanding of the mechanisms that govern their differentiation and function is crucial. This review summarizes our current knowledge of the molecular pathways that regulate CD8 T cell heterogeneity and function in chronic infection and cancer and outlines how T cells respond to therapeutic checkpoint blockade. We explore how T cell-intrinsic and -extrinsic factors influence CD8 T cell differentiation, fate choices, and functional states and ultimately dictate their response to therapy. Identifying cells that orchestrate long-term antitumor immunity and understanding the mechanisms that govern their development and persistence are critical steps toward improving cancer immunotherapy.
Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.
Metazoans have evolved innate antimicrobial defenses that promote cellular survival and proliferation. Countering the inevitable molecular mechanisms by which microbes sabotage these pathways, multicellular organisms rely on an alternative, perhaps more ancient, strategy that is the immune equivalent of suicide bombing: Infection triggers cell death programs that summon localized or even systemic inflammation. The study of human genetics has now unveiled a level of complexity that refutes the naive view that cell death is merely a blunt instrument or an evolutionary afterthought. To the contrary, findings from patients with rare diseases teach us that cell death-induced inflammation is a sophisticated, tightly choreographed process. We herein review the emerging body of evidence describing a group of illnesses-inborn errors of cell death, which define many of the molecular building blocks and regulatory elements controlling cell death-induced inflammation in humans-and provide a possible road map to countering this process across the spectrum of rare and common illnesses.
