Annual review of immunology最新文献

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 perineurial 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.

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 CMV-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.

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, 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.

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.

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.

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.

"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 adaptation of macrophages-the most common tissue-resident immune cells-to metabolic and microbial cues with high local variability is essential for the maintenance of organ integrity. In homeostasis, macrophages show largely predictable tissue-specific differentiation, as recently revealed by multidimensional methods. However, chronic infections with human-adapted pathogens substantially contribute to the differentiation complexity of tissue macrophages, which has been only partially resolved. Specifically, the response to mycobacterial species-which range from Mycobacterium tuberculosis (with highest specificity for humans, broad organ tropism, yet tissue-specific disease phenotypes) to environmental mycobacteria with humans as accidental hosts-may serve as a paradigm of tissue macrophage adaptation mechanisms. While mycobacterial species-specific tissue preferences are partially related to the mode of acquisition and pathogen characteristics, evolutionary convergence with macrophages driven by metabolic features of the target organ likely contributes to infection resistance and immunopathology. In this review, we unravel the mechanisms of tissue-specific macrophage differentiation and its limitations in mycobacterial infections.

As the site of gas exchange, the lung is critical for organismal survival. It is also subject to continual environmental insults inflicted by pathogens, particles, and toxins. Sometimes, these insults result in structural damage and the initiation of an innate immune response. Operating in parallel, the immune response aims to eliminate the threat, while the repair process ensures continual physiological function of the lung. The inflammatory response and repair processes are thus inextricably linked in time and space but are often studied in isolation. Here, we review the interplay of innate immune cells and nonimmune cells during lung insult and repair. We highlight how cellular cross talk can fine-tune the circuitry of the immune response, how innate immune cells can facilitate or antagonize proper organ repair, and the prolonged changes to lung immunity and physiology that can result from acute immune responses and repair processes.