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The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4 + T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8 + T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.

Background COVID-19 is an infectious disease characterized by multiple respiratory and extrapulmonary manifestations, including gastrointestinal symptoms. Although recent studies have linked gut microbiota to infectious diseases such as influenza, little is known about the role of the gut microbiota in COVID-19 pathophysiology. Methods To better understand the host-gut microbiota interactions in COVID-19, we characterized the gut microbial community and gut barrier function using metagenomic and metaproteomic approaches in 63 COVID-19 patients and 8 non-infected controls. Both immunohematological parameters and transcriptional profiles were measured to reflect the immune response in COVID-19 patients. Results Altered gut microbial composition was observed in COVID-19 patients, which was characterized by decreased commensal species and increased opportunistic pathogenic species. Severe illness was associated with higher abundance of four microbial species (i.e., Burkholderia contaminans , Bacteroides nordii , Bifidobacterium longum , and Blautia sp. CAG 257), six microbial pathways (e.g., glycolysis and fermentation), and 10 virulence genes. These severity-related microbial features were further associated with host immune response. For example, the abundance of Bu. contaminans was associated with higher levels of inflammation biomarkers and lower levels of immune cells. Furthermore, human-origin proteins identified from both blood and fecal samples suggested gut barrier dysfunction in COVID-19 patients. The circulating levels of lipopolysaccharide-binding protein increased in patients with severe illness and were associated with circulating inflammation biomarkers and immune cells. Besides, proteins of disease-related bacteria (e.g., B. longum ) were detectable in blood samples from patients. Conclusions Our results suggest that the dysbiosis of the gut microbiome and the dysfunction of the gut barrier might play a role in the pathophysiology of COVID-19 by affecting host immune homeostasis.

The intestinal immune system is continuously exposed to massive amounts of nanoparticles derived from food. Whether nanoparticles from plants we eat daily have a role in maintaining intestinal immune homeostasis is poorly defined. Here, we present evidence supporting our hypothesis that edible nanoparticles regulate intestinal immune homeostasis by targeting dendritic cells (DCs). Using three mouse colitis models, our data show that orally given nanoparticles isolated from broccoli extracts protect mice against colitis. Broccoli-derived nanoparticle (BDN)-mediated activation of adenosine monophosphate-activated protein kinase (AMPK) in DCs plays a role in not only prevention of DC activation but also induction of tolerant DCs. Adoptively transferring DCs pre-pulsed with total BDN lipids, but not sulforaphane (SFN)-depleted BDN lipids, prevented DSS-induced colitis in C57BL/6 (B6) mice, supporting the role of BDN SFN in the induction of DC tolerance. Adoptively transferring AMPK+/+, but not AMPK−/−, DCs pre-pulsed with SFN prevented DSS-induced colitis in B6 mice, further supporting the DC AMPK role in SFN-mediated prevention of DSS-induced colitis. This finding could open new preventive or therapeutic avenues to address intestinal-related inflammatory diseases via activating AMPK. The intestinal immune system is continuously exposed to massive amounts of nanoparticles derived from food. As proof of concept, in this issue of Molecular Therapy, Deng et al. show that nanoparticles isolated from broccoli extracts protected mice from developing colitis by induction of tolerant dendritic cells through the adenosine monophosphate-activated protein kinase-mediated pathway.

Natural antibodies (nAbs) are most commonly defined as immunoglobulins present in the absence of pathological conditions or deliberate immunizations. Occurrence of nAbs in germ- and antigen-free mice suggest that their production is driven, at least in part, by self-antigens. Accordingly, nAbs are constituted of natural autoantibodies (nAAbs), and can belong to the IgM, IgG, or IgA subclasses. These nAbs provide immediate protection against infection while the adaptive arm of the immune system mounts a specific and long-term response. Beyond immediate protection from infection, nAbs have been shown to play various functional roles in the immune system, which include clearance of apoptotic debris, suppression of autoimmune and inflammatory responses, regulation of B cell responses, selection of the B cell repertoires, and regulation of B cell development. These various functions of nAbs are afforded by their reactivity, which is broad, cross-reactive, and shown to recognize evolutionarily fixed epitopes shared between foreign and self-antigens. Furthermore, nAbs have unique characteristics that also contribute to their functional roles and set them apart from antigen-specific antibodies. In further support for the role of nAbs in the protection against infections and in the maintenance of immune homeostasis, the therapeutic preparation of polyclonal immunoglobulins, intravenous immunoglobulin (IVIG), rich in nAbs is commonly used in the replacement therapy of primary and secondary immunodeficiencies and in the immunotherapy of a large number of autoimmune and inflammatory diseases. Here, we review several topics on nAbs features and functions, and therapeutic applications in human diseases.

In healthy settings, the gut–liver axis allows host–microbiota communications and mediates immune homeostasis through bidirectional regulation. Meanwhile, in diseases, gut dysbiosis, combined with an impaired intestinal barrier, introduces pathogens and their toxic metabolites into the system, causing massive immune alternations in the liver and other extrahepatic organs. Accumulating evidence suggests that these immune changes are associated with the progression of many liver diseases, especially hepatic cirrhosis. Pathogen-associated molecular patterns that originated from gut microbes directly stimulate hepatocytes and liver immune cells through different pattern recognition receptors, a process further facilitated by damage-associated molecular patterns released from injured hepatocytes. Hepatic stellate cells, along with other immune cells, contribute to this proinflammatory and profibrogenic transformation. Moreover, cirrhosis-associated immune dysfunction, an imbalanced immune status characterized by systemic inflammation and immune deficiency, is linked to gut dysbiosis. Though the systemic inflammation hypothesis starts to link gut dysbiosis to decompensated cirrhosis from a clinical perspective, a clearer demonstration is still needed for the role of the gut–liver–immune axis in cirrhosis progression. This review discusses the different immune states of the gut–liver axis in both healthy and cirrhotic settings and, more importantly, summarizes the current evidence about how microbiota-derived immune remodeling contributes to the progression of hepatic cirrhosis via the gut–liver axis.

The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.

The oral microbiome comprises over 700 distinct species, forming complex biofilms essential for maintaining oral and systemic health. When the microbial homeostasis in the periodontium is disrupted, pathogens within the biofilm can cause periodontitis and peri-implantitis, inducing host immune responses. Understanding the role of microbial communities and the immune mechanisms in oral health and disease is crucial for developing improved preventive, diagnostic and therapeutic strategies. However, many questions remain about how changes in bacterial populations contribute to the development and progression of these conditions. An electronic and manual literature search was conducted using PubMed, Excerpta Medica, Frontiers Reports and the Wiley Online Library databases for relevant articles. Data from these publications were extracted and the overall findings were summarized in a narrative manner. The variations in microbial communities and immune responses of periodontitis and peri-implantitis are explored. Dysbiosis of the subgingival microbiome—characterized by an increase in pathogenic bacteria such as Porphyromonas gingivalis , Tannerella forsythia , and Aggregatibacter actinomycetemcomitans —plays a pivotal role in the initiation and progression of periodontitis. As for peri-implantitis, alterations include a higher abundance of opportunistic pathogens and reduced microbial diversity around implants. Moreover, oral dysbiosis potentially influencing systemic health through immune-mediated pathways. Regional immunity of periodontium involving neutrophils, T helper cells-17, and immune-related cytokines is crucial for maintaining periodontal homeostasis and responding to microbial imbalances. Additionally, the impact of non-mechanical treatments—such as probiotics and laser therapy—on the oral microbiome is discussed, demonstrating their potential in managing microbial dysbiosis. These findings underscore that bacterial dysbiosis is a central factor in the development of periodontitis and peri-implantitis. Maintaining microbial balance is essential for preventing these diseases, and interventions targeting the microbiome could enhance treatment outcomes. Strategies focusing on controlling pathogenic bacteria, modulating immune responses, and promoting tissue regeneration are key to restoring periodontal stability. Further research is needed to clarify the mechanisms underlying the transition from peri-implant mucositis to peri-implantitis and to optimize prevention and treatment approaches, considering the complex interactions between the microbiome and host immunity.

[This corrects the article DOI: 10.3389/fimmu.2025.1696932.].

The TGFβ superfamily is composed of more than 33 growth and differentiation factors, including TGFβ1, β2, β3, BMPs, GDFs, nodal-related proteins, and activins. These members usually exert pleiotropic actions on several tissues and control multiple cellular processes, such as cell growth, cell survival, cell migration, cell fate specification, and differentiation, both during embryonic development and postnatal life. Although the effects of these factors on immune responses were elucidated long ago, most studies have been focused on the actions of TGFβs on T cells, as major regulators of adaptive immunity. In this review, we discuss new findings about the involvement of TGFβ superfamily members in the control of B cell development and function. Moreover, the potential contribution of TGFβ signaling to control B cell-mediated autoimmune diseases and its utility in the design of new therapies are also discussed.

Methyltransferase-like 3(METTL3), recognized as the primary N 6 -methyladenosine methyltransferase, influences cellular functions such as proliferation, migration, invasion, differentiation, and fate determination by regulating gene expression post-transcriptionally. Recent studies have highlighted the indispensability of METTL3 in various immune cells such as hematopoietic stem/progenitor cells, innate immune cells (monocytes, macrophages, dendritic cells), and adaptive immune cells (thymic epithelial cell, T cells, natural killer cells). However, a comprehensive summary and analysis of these findings to elucidate the relationship between METTL3 and the immune system is yet to be undertaken. Therefore, in this review, we systematically collate reports detailing the mechanism underlying the role of METTL3 in regulating various immune processes and examine the modification of METTL3 and its potential implications. This review suggests that METTL3 plays an essential role in the immune system, ranging from maintaining homeostasis to regulating functions. Collectively, this review provides a comprehensive analysis of the relationship between METTL3 and the immune system, serving convenient researchers to understand the frontiers of immunological research and facilitate future clinical applications.