Immunology & Cell Biology最新文献

This Special Feature brings you the “Highlights of 2024”, a collection of short articles to bring you up to date on major advances in immunology research published in 2024. Each highlight article summarizes the key papers that drove new discoveries in a specific area of immunology. Pankhurst and Linterman¹ highlight the latest discoveries in the germinal center response and new opportunities for the development of more effective vaccines and immunotherapies. Flaman et al.² focus on key studies that provide critical insights into the development, differentiation, and longevity of antibody secreting cells in health and disease. In Lee and Reed,³ we review recent findings on age-associated B cells, the discovery of their transcriptional regulator, and the evidence for a pathogenic role in autoimmune disease. Valentini et al.⁴ discuss metabolic pathways that alter regulatory T-cell function and differentiation and their potential as therapeutic targets in inflammatory niches, tumors and autoimmune disease. McEwan et al.⁵ update us on the growing evidence that the most important risk gene for Alzheimer's disease, the apolipoprotein E variant, APOE4 drives immune dysregulation causing neuroinflammation and neurodegeneration. Eberl⁶ summarizes the role of γδ T cells in tissues during sepsis while referring to 58 Taylor Swift song titles—how many can you find? 2024 was also a big year for innate lymphoid cells (ILC), with Shen et al.⁷ discussing tissue-specific roles for ILC3, highlighting metabolic and checkpoint molecules as targets for immunotherapy. Shajan et al.⁸ summarizes the critical signaling pathways, epigenetic modifications and cytokines-regulating natural killer (NK) cell function and survival. Bourel et al.⁹ review the latest strategies to enhance NK cell cytotoxicity and memory for cell-based cancer therapy. Finally, Jose et al.¹⁰ discuss advances and clinical trials for antibody–drug conjugates, which combine monoclonal antibody specificity with cytotoxic agents to selectively deliver potent drugs to tumor cells.

Whether you are reliving some of 2024's key findings in your field or learning about the major advances in another area, this Special Feature will get you up to date and ready for another exciting year or immunology.

The author declares no conflicts of interest.

Joanne H Reed: Conceptualization; writing – original draft; writing – review and editing.

CD4⁺ T cells play a vital role in the occurrence and development of autoimmune diseases (AID). The differentiation direction and function of CD4⁺ T cells are both regulated by metabolic reprogramming, which differs across various CD4⁺ T subsets. Glutamine (Gln), as an immunoregulatory nutrient, not only provides bioenergy and biosynthesis for the differentiation and effector function of CD4⁺ T cells but also regulates intracellular redox conditions and produces metabolic intermediates that are used for epigenetic modification of effector cell genes. Here, we review the metabolic characteristics of Gln in CD4⁺ T cells and its regulatory effects on CD4⁺ T-cell differentiation and function. We also summarize potential targets on Gln metabolism for AID therapy, including Gln transporters, Gls1, GSH synthesis and epigenetic modification. However, the primary challenge remains how to achieve cell type-specific metabolic inhibition in vivo. Therefore, future research should focus on developing selective and effective therapeutic agents that modulate Gln metabolism while minimizing cytotoxicity for AID treatment.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract believed to arise from an imbalance between its epithelial, immune and microbial components. It has been shown that biological differences (e.g. genetic, epigenetic, microbial, environmental) exist between patients with IBD. It is also known that there is important heterogeneity in the response to therapies that target very specific biological pathways (e.g. TNF-alpha signaling, IL-23R signaling, immune cell trafficking). The aim of this study was to identify potential biological differences associated with differential treatment response to the anti α4β7 integrin therapy known as vedolizumab. We performed targeted analyses of > 150 proteins and metabolites, and nontargeted analyses of > 1100 lipid entities in serum samples from 92 IBD patients (42 CD, 50 UC) immediately prior to initiation of therapy with vedolizumab (baseline samples) and at their first clinical assessment (week 14 samples). We detected that the baseline levels of multiple serum cytokines, amino acids, acylcarnitines and triglycerides were different between responders and nonresponders to treatment with vedolizumab. We also noted changes in serum analytes between baseline and week 14 samples that were different between these two groups of patients. Many of these serum analytes are markers of biological pathways that are involved in the activation, proliferation and metabolism of pro-inflammatory cells. This study provides support for the hypothesis that biological differences between individuals not only impact the risk to develop IBD and IBD-related clinical phenotypes but also an IBD patient's likelihood of responding to a biological therapy.

Type-2 dendritic cells (DC2s) are essential for the initiation of type-2 immune responses, but the signaling pathways involved in allergen sensing, DC activation and instruction of CD4⁺ T cell differentiation into T_H2 cells remain unclear. Previous studies demonstrated a type-I interferon (IFN-I) signature in skin DC2s following immunization with non-viable larvae of the helminth Nippostrongylus brasiliensis (Nb), house dust mite (HDM) or Schistosoma egg antigen (SEA). Here we show that conditional loss of IFNAR1 signaling in CD11c⁺ DCs significantly impaired T_H2 effector and T follicular helper (TFH) CD4⁺ T cell responses to Nb. In vivo proliferation experiments demonstrated reduced numbers of highly divided CD4⁺ T cells in IFNAR1^∆CD11c mice compared to IFNAR1^WT, with similar proportions of GATA3^hi T_H2 cells within the divided populations indicating that IFNAR1 signaling in DCs was supporting T cell priming and expansion rather than GATA3^hi differentiation. By contrast, TFHs were present in lower frequencies in IFNAR1^∆CD11c mice compared to IFNAR1^WT, suggesting that IFN-I signaling in DCs is necessary for allergen-specific TFH differentiation. Characterization of the DC2 compartment by flow cytometry and bulk RNAseq demonstrated lower numbers of Nb⁺ DC2s in draining lymph nodes (dLN) and reduced expression of genes involved in DC2 motility, focal adhesion, and antigen processing, while expression of costimulatory molecules and cell survival and apoptosis pathway scores were similar. Therefore, IFN-I conditioning of skin DC2s is necessary for their effective priming of CD4⁺ T_H2 responses to allergens and likely acts through the additive effects of multiple IFN-I-regulated pathways in DC2s.

In this article for the Highlights of 2024 Series, we discuss strategies to enhance NK cell-based cancer therapies. These include (1) cytokine expression on bacterial membranes to boost NK cell activation in tumors, (2) optimizing CAR-NK cell manufacturing for improved efficacy, (3) using CRISPR-Cas9 to identify and target inhibitory genes, and (4) using tetraspecific engagers to enhance cytotoxicity and cytokine memory-like NK cells strengthening anti-tumor responses. This year's progress holds much promise for cancer treatments exploiting NK cells.

Immune cells interact directly with other cells and make decisions by integrating information from many different receptor–ligand interactions at these cell–cell interfaces. Since they encounter a huge variety of normal and abnormal cells, they experience many different combinations and concentrations of ligands. Understanding immune responses therefore requires platforms that enable ligands to be easily manipulated. We review and compare the available platforms, focusing on T-cell recognition. Although genetically modified antigen-presenting cells (APCs) offer the most physiological system, manipulating their ligands is difficult and slow. In contrast, solid surfaces or supported lipid bilayers allow easy manipulation of ligands but lack the biophysical properties of cells, such as softness, a glycocalyx, and/or ligand mobility. A recently developed CombiCell system enables easy manipulation of ligands while conserving key biophysical properties. By comparing the advantages and limitations of each platform, we provide a framework to choose the most suitable system to study signal integration in both basic and translational contexts.

In this article for the Highlights of 2024 series, we review the latest advances in the biology of the germinal center response. These discoveries provide key insights into germinal center function and dysregulation, uncovering new opportunities for the development of more effective vaccines.

Founded in 2005, Gallipoli Medical Research (GMR) is a leading independent medical research institute located in Greenslopes, Brisbane, Queensland. GMR strives to enrich and restore lives through pioneering medical research that transcends the laboratory to deliver meaningful and tangible real-world solutions. In 2006, GMR launched its clinical trials program at one of Australia's largest private hospitals, with the focus on advancing healthcare through innovative treatments and emerging therapies, with a particular focus on oncology, liver, and respiratory diseases. Dr Suzanne Elliott is the Associate Director of Clinical Trials at GMR. Here, Dr Elliott discusses her transition from laboratory-based research into the clinical trial industry and shares her insight, advice, and pioneering contributions to industry, government, and the clinical trial research landscape across her diverse 30-year career.

T follicular regulatory (Tfr) cells have emerged as key mediators in controlling germinal center (GC) responses, preventing excessive immune activation and preserving self-tolerance. Initially thought to originate solely from thymic T regulatory cells (tTregs), recent findings reveal a more complex picture involving multiple differentiation pathways contributing to their heterogeneity. The natural route of differentiation comprises the most abundant subset, which originates from tTregs and retains the expression of CD25 (CD25⁺ nTfr), before transitioning into a more mature CD25-negative state within the GC (CD25⁻ nTfr). Conversely, the induced route (iTfr) includes Tfr cells that arise alongside nTfr cells but originate from peripheral Tregs or CD25-expressing Tfh cells, in addition to a late-GC subset (late Tfr) that emerges through the expression of FoxP3 by Tfh cells. The identification of circulating Tfr cells (cTfr) in peripheral blood, especially useful for studying immune dysregulation in humans, provides insights into their systemic roles and potential as biomarkers for immune dysfunction in different clinical scenarios. While it becomes evident that Tfr cells exhibit a heterogeneous nature, a deeper understanding of their distinct subsets could pave the way for targeted immunomodulatory strategies in the development of novel vaccines and therapeutics. This review provides a comprehensive overview of Tfr cell diversity, exploring their ontogeny, functional roles, and impact on immune homeostasis and disease.

Crohn's disease is a chronic, transmural inflammatory disease of the human gut. Changes in the fecal microbial composition and dysbiosis are consistent features in studies of Crohn's disease patients, but whether dysbiosis is a cause or consequence of inflammation remains unresolved. Genetic susceptibility plays a role in the development of Crohn's disease and has been linked to genes involved in recognition of intestinal bacteria by the mononuclear phagocyte system. The earliest visible lesions in Crohn's disease are aphthous ulcers, overlying Peyer's patches and lymphoid follicles. To identify mechanisms underlying the earliest stages of disease we compared gene expression in aphthous ulcers, Peyer's patches, inflamed and endoscopically normal mucosa from patients and controls using total RNA-seq. The resulting data were subjected to network analysis to identify coregulated gene expression signatures of cell types and processes. These results were compared to single-cell RNA-seq analysis of intestinal macrophages in normal and diseased mucosa. The analysis of aphthous ulcers revealed signatures of epithelial stress and antimicrobial defense, plasma cell activation and immunoglobulin production, monocyte recruitment, inflammatory gene expression and induction of interferon-γ. These signatures were not present in the normal appearing mucosa adjacent to aphthous ulcers, which were similar to healthy control mucosa. Given the role of Peyer's patches and lymphoid follicles in sampling the luminal contents, these findings suggest the initial lesion in Crohn's disease arises from the uptake of bacteria and the activation of multiple host defense pathways rather than the breakdown of epithelial barrier integrity and widespread bacterial translocation.