We use mathematical modeling to study the proliferation dynamics of CD4+ T cells within an immune response. This proliferation is driven by the autocrine reaction of helper T cells and interleukin-2 (IL-2), and regulated by natural regulatory T cells (nTregs). Previous studies suggested that a fratricidal mechanism is necessary to eliminate helper T cells post-infection. Contrary to this, our mathematical analysis establishes that the depletion of these cells is due to two pivotal factors: the saturation in the proliferation rate of helper CD4+ T cells at high IL-2 concentrations, and the activation rate of nTregs outpacing their death rate. This yields an excitable process, such that the proliferation starts once the helper T cell population passes a threshold. Additionally, we find that when the proliferation of nTregs lags behind their mortality, induced regulatory T cells (iTregs) are crucial to curbing the proliferation of helper CD4+ T cells.

Multiple sclerosis (MS) is a chronic neurological disorder derived from autoreactive immune system attacking the protective myelin sheath that surrounds nerves in the central nervous system (CNS). Here, a tolerogenic nanovaccine for generating an antigen-specific immune tolerance for treating MS is proposed. It consisted of a mesoporous polydopamine (mPDA) nanoparticle, characterized by high reactive oxygen species (ROS)-scavenging property, loaded with MS-derived autoantigen. Intravenous vaccination of autoantigen-loaded mPDA could induce tolerogenic dendritic cells (DCs) with low expression of co-stimulatory molecules while presenting peptide epitopes. The tolerogenic DCs induced peripheral regulatory T-cells (Tregs), thereby reducing infiltration of autoreactive CD4+ T-cells and inflammatory antigen-presenting cells (APCs) into the CNS. In MS-mimicking mouse model, the tolerogenic nanovaccine prevented MS development in the early therapeutic setup and exhibited an enhanced recovery from complete paralysis in the late therapeutic model. The current platform could be exploited to treat other autoimmune diseases where disease-dependent autoantigen peptides are delivered.

We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.

A recent study conducted by the laboratory of the first author revealed that major depression is composed of two distinct subtypes: major dysmood disorder (MDMD) and simple dysmood disorder (SDMD). The latter is a less severe phenotype with fewer aberrant biological pathways. MDMD, but not SDMD, patients were identified to have highly sensitized cytokine/growth factor networks using stimulated whole blood cultures. However, no information regarding serum cytokines/chemokines/growth factors in SDMD is available.

This case-control study compares 48 serum cytokines/chemokines/growth factors in academic students with SDMD (n = 64) and first episode (FE)-SDMD (n = 47) to those of control students (n = 44) using a multiplex assay.

Both FE-SDMD and SDMD exhibited a notable inhibition of immune profiles, such as the compensatory immunoregulatory response system (CIRS) and alternative M2 macrophage and T helper-2 (Th-2) profiles. We observed a substantial reduction in the serum concentrations of five proteins: interleukin (IL)-4, IL-10, soluble IL-2 receptor (sIL-2R), IL-12p40, and macrophage colony-stimulating factor. A considerable proportion of the variability observed in suicidal behaviors (26.7 %) can be accounted for by serum IL-4, IL-10, and sIL-2R (all decreased), CCL11 (eotaxin) and granulocyte CSF (both increased). The same biomarkers (except for IL-10), accounted for 25.5 % of the variance in SDMS severity. A significant correlation exists between decreased levels of IL-4 and elevated ratings of the brooding type of rumination.

SDMD is characterized by the suppression of the CIRS profile, which signifies a disruption of immune homeostasis and tolerance, rather than the presence of an inflammatory response.

The age-related decline in immunity appears to be associated not only with cancer development but also with differential responses to immune checkpoint inhibitors (ICIs). Despite their increasing utility across various malignancies and therapeutic settings, limited data -derived primarily from subgroup analyses of randomized controlled trials (RCTs), pooled meta-analyses, and retrospective studies- are available on the effects of aging on their efficacy and toxicity. Immunosenescence, characterized by the progressive decline of the function of the immune system, and inflammaging, a state of persistent low-grade sterile inflammation, may influence ICI outcomes. Additionally, the incidence, severity, and subtypes of immune-related adverse events (irAEs) may differ between older and younger individuals due to loss of immunotolerance. In the current review, starting from a a comprehensive discussion of the pathophysiology of immunosenescence, we proceed to critically review age-related retrospective and randomized evidence supporting FDA-approved ICIs. We highlight similarities or differences across age groups and the clinical benefit of ICIs in elderly versus younger cancer patients. The optimal integration of ICIs in geriatric oncology necessitates greater inclusion of this patient demographic in RCTs along with real-world data in order to acquire robust data which will guide evidence-based treatment decisions for this population.

Anti-glomerular basement membrane (anti-GBM) disease is accompanied by insufficient antigen-specific regulatory T cells (Tregs) and clonally expanded antigen-specific conventional T cells. In particular, this applied to the immunodominant T cell autoepitope of type IV collagen, α3(IV)NC1135-145, presented by human leukocyte antigen-DRB1∗1501. Here, we investigated whether Tregs engineered to express GBM-T cell receptors (TCR) specific for α3(IV)NC1135-145 better suppress autoimmunity. The GBM-TCR Treg cell product exhibited a phenotypically stable Treg phenotype, produced α3(IV)NC1135-145-specific functional responses, and were superior suppressors of autoreactive conventional T cells and bystander conventional T cells compared to polyclonal Tregs or irrelevant TCR-transduced Tregs. We also found that GBM-TCR Tregs modulate other immune cells like dendritic cells and B cells to a more tolerogenic phenotype. Importantly, our findings support the development of GBM-TCR Tregs as a promising cell-based therapy for anti-GBM disease.

The abscopal effect in radiotherapy (RT) refers to the phenomenon where localized radiation treatment causes regression of distant, nonirradiated tumors. Although rare, recent research shows that combining radiation with immunotherapies, such as immune checkpoint inhibitors, can enhance this effect. The interaction between radiation-induced cell death, immune responses, and the tumor microenvironment manifests in competing biologic mechanisms resulting in complex immunologic outcomes. In order to maximize the therapeutic advantages of the immunogenic effect of RT in the future, further studies are needed to fully understand its biologic underpinnings.

The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a 5-year survival rate of only 12.5%. Early detection of PDAC or addressing risk factors for PDAC development are ways to improve outcomes. PDAC can arise from precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and less frequent, mucinous cystic neoplasm (MCN), and other rare precursor variants. High-risk precursor lesions harbor a substantial chance of evolving into PDAC. Such lesions can often be found in resected PDAC specimens adjacent to the cancer. Unfortunately, recognizing precursor lesions that need to be resected is often tricky, and resections frequently end in major surgical interventions. Thus, better ways to handle precursor lesions are desperately needed. We mapped the immune microenvironments (IMEs) of PanINs, IPMNs, and MCNs on a cellular level using multiplex immunofluorescence and computational imaging technology and compared the findings to PDACs and normal pancreatic tissues. We found distinct and potentially targetable mechanisms of immunosuppression between the two main precursor lesions, PanIN and IMPN. Immunosuppression in IPMNs seems partly mediated by programmed cell death protein 1 ligand (PD-L1) expression on antigen-presenting cells (APCs). By contrast, elevated numbers of regulatory T cells (Tregs) seem to be key players in the immunosuppression of PanINs. Thus, treating high-risk IPMNs with anti-PD-1 and high-risk PanINs with agents targeting Tregs, such as anti-lymphocyte associated protein 4 (anti-CTLA-4) antibodies, could reverse their immunosuppressive state. Reversal of immunosuppression will restore immunosurveillance and eventually prevent progression into PDAC. We also review relevant published and ongoing non-surgical treatment approaches for high-risk IPMNs and PanINs.

Colorectal cancer is a major global health burden, with significant heterogeneity in clinical outcomes among patients. Identifying robust prognostic gene expression signatures can help stratify patients, guide treatment decisions, and improve clinical management. This review provides an overview of current prognostic gene expression profiles in colorectal cancer research. We have synthesized evidence from numerous published studies investigating the association between tumor gene expression patterns and patient survival outcomes. The reviewed literature reveals several promising gene signatures that have demonstrated the ability to predict disease-free survival and overall survival in CRC patients, independent of standard clinicopathological risk factors. These genes are crucial in fundamental biological processes, including cell cycle control, epithelial-mesenchymal transition, and immune regulation. The implementation of prognostic gene expression tests in clinical practice holds great potential for enabling more personalized management strategies for colorectal cancer.

To investigate the significance of regulatory T cells (Tregs) and programmed cell death 1 (PD-1)+ cytotoxic T lymphocytes (CTLs) in the vitreous of patients with vitreoretinal lymphoma (VRL) and uveitis.

This study involved 51 patients with VRL and uveitis, 15 males and 36 females (mean age: 72 years, range: 51-86 years), who underwent vitrectomy at the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan, from December 2019 to February 2024. All patients underwent lymphocyte surface antigen analysis via flow cytometry, and the proportion of Tregs in CD4+ T lymphocytes and PD-1+ CTLs in CD8+ T lymphocytes was measured.

This study involved B cell VRL (B-VRL, n=16), sarcoidosis (n=8), human herpesvirus (HHV)-associated uveitis (n=7), human T cell lymphotropic virus type 1 associated uveitis (HAU, n=3) and unclassifiable uveitis (n=17) cases. The median proportions of Tregs were significantly lower in B-VRL (2.2%) compared with sarcoidosis (8.5%), HHV-associated uveitis (16.4%) and unclassifiable uveitis (10.1%) (p<0.05). Conversely, a significantly higher proportion of PD-1+ CTLs was found in B-VRL (95.6%) compared with sarcoidosis (61.1%), HHV-associated uveitis (67.1%) and unclassifiable (64.8%) (p<0.05). Receiver operating characteristic analysis of Tregs and PD-1+ CTLs proportions in B-VRL revealed high area under the curve values of 0.913 and 0.940, respectively.

Our findings indicate that analysis of the ratio of Tregs and PD-1+ CTLs via flow cytometry is helpful in diagnosing B-VRL.

Various mammalian CD8+ T cell subsets with regulatory properties are either formed through a thymus-dependent mechanism or induced under various experimental protocols and referred to as CD8+ regulatory T cells (Tregs). CD8+ Tregs maintain distinct functions in the presence of CD4+ Tregs. This review focuses on the Foxp3+CD8+ Treg subset, which is typically extremely rare in unmanipulated mice and healthy humans under steady-state conditions. However, they can be induced and expanded for transplantation, autoimmune diseases, cancer, viral infections, and T cell receptor transgenic adoptive cell transfer models. Here, we summarize recent research progress related to this population, including the identification of phenotypic markers, induction determinants, and functional activities. Additionally, we discuss advances in manipulating Foxp3+CD8+ Tregs in autoimmunity and transplantation.

The discovery of interleukin-2 (IL-2) and its receptor (IL-2R) almost 50 years ago revolutionized immunology, marking a pivotal moment in understanding T cell biology and immune regulation. Initially identified as a T cell growth factor, IL-2 unveiled critical insights into cytokine-mediated immune cell proliferation and differentiation.

This review highlighted the characterization of IL-2R as a multi-chain receptor complex set a precedent for decoding cytokine receptor signaling. The unique interplay between IL-2 and its high-affinity receptor component, IL-2Rα, epitomizes the principle of specificity and efficiency in cytokine signaling, enabling precise immune modulation. Regulatory T cells (Tregs) exploit IL-2Rα high affinity to outcompete effector T cells for IL-2, ensuring immune tolerance and preventing autoimmunity.

Despite its foundational role in immune homeostasis, leveraging IL-2 for therapeutic purposes has proven challenging.

IL-2-based therapies hold transformative potential in autoimmunity, cancer immunology, and transplantation, yet they remain elusive due to the complex balance between immunostimulatory and immunosuppressive effects. This review explores the milestones in IL-2 biology, its dualistic functions, and the ongoing quest to harness its therapeutic promise.

Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance by suppressing immune responses against pathogens. The fluctuation of Treg proportions in COVID-19 remains a topic of debate, and the mechanisms triggering Treg activation in COVID-19 are still unclear. Understanding these issues is essential for better managing immune responses in COVID-19 patients.

We collected a cohort of COVID-19 patients with varying disease severity and stage to explore the transcriptomic and functional traits of Tregs in these individuals. Using transcriptomic analysis, we evaluated the proportion and functionality of different Treg subsets, specifically HLA_DR+ Tregs, across different stages of COVID-19 patients.

Our analysis revealed that the proportion of CCR7 + Tregs decreased as the disease advanced, while the cell proportion of HLA_DR+ regs escalated with the severity of the disease. Moreover, the transcription actor CARHSP1 exhibited apositive correlation with the proportion of HLA_DR+ Tregs. Notably, the heightened suppressive function of HLA_DR+ Tregs in severe COVID-19 patients, with interactions between PF4 and CXCR3, contributed to the homeostasis of HLA_DR+ Tregs in severe COVID-19 patients. Furthermore, we observed that Tregs in COVID-19 patients exhibited weakened TCR clonotype expansion, and the suppression of HLA_DR+ Tregs with expanded TCR clonotypes in severe COVID-19 cases did not show a significant increase compared to asymptomatic and mild COVID-19 groups. The findings indicate that Tregs may be activated through the bystander effect, as evidenced by the analysis of TCR clonotype characteristics.

Our research delineates the diversity of dynamic alterations in Tregs and sheds light on potential mechanisms underlying Treg activation, providing a theoretical foundation and offering treatment strategies for managing COVID-19 patients.

Regulatory T cells (Tregs) are key regulators in maintaining tissue homeostasis. Disrupted immune homeostasis is associated with Crohn's disease (CD) pathogenesis. Thus, Treg therapy represents a promising long-acting treatment to restore immune balance in the diseased intestine. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer treatment. This innovative approach also provides the opportunity to improve therapy for CD. By targeting a disease-relevant protein, interleukin-23 receptor (IL23R), we engineered Tregs expressing IL23R-CAR for treating active CD.

Intestinal IL23R expression from active CD was verified by immunohistochemical analysis. Phenotypic and functional characteristics of IL23R-CAR Tregs were assessed using in vitro assays and their migration capacity was monitored in a xenograft tumor model. Transcriptomic and proteomic analyses were performed to associate molecular profiles with IL23R-CAR Treg activation against colon biopsy-derived cells from active CD patients.

Our study showed that IL23R-CAR displayed negligible tonic signaling and a strong signal-to-noise ratio. IL23R-CAR Tregs maintained regulatory phenotype during in vitro expansion, even when chronically exposed to proinflammatory cytokines and target antigen. IL23R engagement on IL23R-CAR Tregs triggered CAR-specific activation and significantly enhanced their suppressive activity. Also, IL23R-CAR Tregs migrated to IL23R-expressing tissue in humanized mice. Finally, IL23R-CAR Tregs elicited a specific activation against colon biopsy-derived cells from active CD, suggesting an efficient CAR engagement in active CD. Molecular profiling of CD patient biopsies also revealed transcriptomic and proteomic patterns associated with IL23R-CAR activation.

Overall, our results demonstrate that IL23R-CAR Tregs represent a promising therapy for active CD.

High-grade gliomas (HGGs), including glioblastoma (GBM) in adults and diffuse intrinsic pontine glioma (DIPG) in children, are among the most aggressive and deadly brain tumors. A key factor in their resilience is the presence of glioma stem cells (GSCs), which drive tumor initiation, progression, and resistance to treatment. Targeting and eradicating GSCs holds potential for curing both GBM and DIPG. Natural killer (NK) cells, as part of the innate immune system, naturally recognize and destroy malignant cells. Recent advances in NK cell-based therapies, such as chimeric antigen receptor (CAR)-NK cells, NK cell engagers, and NK cell-derived exosomes, offer promising approaches for treating GBM and DIPG, particularly by addressing the persistence of GSCs. This review highlights these advancements, explores challenges such as the blood-brain barrier and the immunosuppressive tumor microenvironment, and proposes future directions for improving and clinically advancing these NK cell-based therapies for HGGs.

Breast cancer (BC) is a common malignant tumor in women, and cancer-related fatigue (CRF) is prevalent among breast cancer patients. Time-Acupoints-Space Acupuncture (ATAS) is an acupuncture method different from traditional acupuncture. It combines time acupoints with space acupoints, proposing a new treatment approach. This randomized controlled trial aims to evaluate whether ATAS can improve fatigue in postoperative chemotherapy patients with breast cancer.

This randomized controlled trial focuses on survivors of postoperative chemotherapy for breast cancer, primarily assessing whether ATAS can reduce fatigue in these patients. Additionally, it reports on the effects of ATAS on sleep, anxiety, depression, and inflammatory factors.

The researchers randomly assigned 90 postoperative breast cancer patients to the ATAS group (n=30), the sham acupuncture group (n=30), and the waitlist control group (n=30). The primary outcome was the Piper Fatigue Scale (PFS), and the secondary outcomes were the Insomnia Severity Index (ISI), Hospital Anxiety and Depression Scale (HADS), Interleukin-2 (IL-2), Interleukin-6 (IL-6), CD3+T, and CD4+T. Data analysis was performed using the statistical software SPSS, utilizing descriptive statistics and analytic statistics. The significance level was set at less than 0.05.

The baseline differences in PFS scores among the three groups were not statistically significant (P > 0.05). ATAS treatment is superior to sham acupuncture and the waitlist control in improving fatigue (mean difference 4.98, 95% CI 3.96 to 6.00, P<0.05). Additionally, secondary outcome analysis shows that the ATAS group has positive effects on ISI, HADS, and inflammatory factors. After the treatment ended, ISI (mean difference 15.17, 95% CI 12.28 to 18.06, P<0.05), HADS-A (mean difference 8.63, 95% CI 5.18 to 12.08, P<0.05), HADS-D (mean difference 7.80, 95% CI 4.73 to 10.87, P<0.05). IL-2(mean difference 20.18, 95% CI 11.51 to 28.85, P<0.05), IL-6(mean difference 24.56, 95% CI 7.57 to 41.55, P<0.05), CD3+T(mean difference 79.03, 95% CI 68.56 to 89.50, P<0.05), CD4+T(mean difference 42.89, 95% CI 35.14 to 50.64, P<0.05).

Our preliminary findings indicate that ATAS effectively improves fatigue in postoperative chemotherapy patients with breast cancer. It also has positive effects on sleep, anxiety, depression, and inflammatory factors. These results suggest that ATAS intervention may be an effective method for alleviating fatigue in breast cancer patients.

https://www.chictr.org.cn/showproj.html?proj=21999, identifier ChiCTR17013652.

The balance between CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) plays a crucial role in the immune checkpoint inhibition (ICI) therapy in gastric carcinoma (GC). However, related factors leading to the disturbance of TME and resistance to ICI therapy remain unknown. In this study, we applied N6-methyladenosine (m6A) small RNA Epitranscriptomic Microarray and screened out 3'tRF-AlaAGC based on its highest differential expression level and lowest inter-group variance. N6-methyladenosine modification significantly enhanced the stability of 3'tRF-AlaAGC, which strengthened glycolysis and lactic acid (LA) production in GC cells by binding to PTBP1 (Polypyrimidine Tract Binding Protein 1). In the peritoneal GC implantation model established in huPBMC-NCG mice, 3'tRF-AlaAGC significantly increased the proportion of PD1+ Treg cells. Furthermore, in high-LA environments driven by glucose consumption of GC cells, Treg cells actively uptake LA through MCT1, facilitating NFAT1 translocation into the nucleus and enhancing PD1 expression, whereas PD1 expression by effector T cell is diminished. Meanwhile, T cell suppression assays were performed under low-LA or high-LA conditions, and the proliferation of CD8+ T cells was dampened by adding Sintilimab in a high-LA but not in a low-LA environment, suggesting the preferential activation of PD1+ Treg cell. These findings deciphered the complexities of the immune microenvironment in GC, providing prospects for identifying robust biomarkers that could improve the evaluation of therapeutic effectiveness and prognosis in immune therapy for GC.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes across several solid tumour types. Prominent efforts have focused on understanding the anticancer mechanisms of these agents, identifying biomarkers of response and uncovering resistance mechanisms to develop new immunotherapeutic approaches. This research has underscored the crucial roles of the tumour microenvironment and, particularly, tumour-infiltrating lymphocytes (TILs) in immune-mediated tumour elimination. Numerous studies have evaluated the prognostic and predictive value of TILs and the mechanisms that govern T cell dysfunction, fuelled by technical developments in single-cell transcriptomics, proteomics, high-dimensional spatial platforms and advanced computational models. However, questions remain regarding the definition of TILs, optimal strategies to study them, specific roles of different TIL subpopulations and their clinical implications in different treatment contexts. Additionally, most studies have focused on the abundance of major TIL subpopulations but have not developed standardized quantification strategies or analysed other crucial aspects such as their functional profile, spatial distribution and/or arrangement, tumour antigen-reactivity, clonal diversity and heterogeneity. In this Review, we discuss a conceptual framework for the systematic study of TILs and summarize the evidence regarding their biological properties and biomarker potential for ICI therapy. We also highlight opportunities, challenges and strategies to support future developments in this field.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4+ Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.

Omalizumab (XOLAIR®)-assisted multi-food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab-assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab-assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab-assisted mOIT.

Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high-dimensional cytometry-based single-cell data and high-throughput multiplex cytokine data.

Our results demonstrated that the frequency of HLA-DR+ Treg cells, and the production of Th2 cytokines (IL-4, IL-5, IL-13, and IL-9) as well as the immunoregulatory cytokine IL-10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA-DR+ Treg cells and enhanced production of IL-10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab-assisted mOIT inducing a significant reduction in the production of Th2 cytokines.

We demonstrated that the frequency of HLA-DR+ Treg cells and IL-10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab-assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.

It has been reported that the nervous system can regulate immune reactions through various mechanisms. However, the role of splenic sympathetic nerve activity in the autoimmune reactions during the pathogenesis of experimental autoimmune encephalomyelitis (EAE) remained unclear. Here, we blocked the activity of the splenic sympathetic nerve and found that the number of adaptive immune cells, such as CD4+ T cells, CD8+ T cells and B cells, were upregulated. Additionally, there was an increase in the secretion of inflammatory cytokines in the spleen, and the neurological symptoms of EAE were exacerbated. In vitro experiments, we found that norepinephrine (NE), the neurotransmitter of the splenic sympathetic nerve, indirectly drove the death of effector CD8+ T cells. Furthermore, activated B cells, under the influence of NE, specifically recognized effector CD8+ T cells by upregulating MHC-I molecules and killed these cells via the FasL/Fas pathway. Our findings provide a new perspective on B cells killing effect in vitro, which was boosted by NE and demonstrate that the splenic sympathetic nerve controls the degree of autoimmune responses in EAE. This adds a new dimension to the diversity of NE's regulatory effects on adaptive immune cells and suggests a potential new therapeutic approach for autoimmune diseases.

Transfusion-related acute lung injury (TRALI) is a potentially lethal complication of blood transfusions, characterized by the rapid onset of pulmonary edema and hypoxemia within six hours post-transfusion. As one of the primary causes of transfusion-related mortality, TRALI carries a significant mortality rate of 6-12%. However, effective treatment strategies for TRALI are currently lacking, underscoring the urgent need for a comprehensive and in-depth understanding of its pathogenesis. This comprehensive review provides an updated and detailed analysis of the current landscape of TRALI, including its clinical presentation, pathogenetic hypotheses, animal models, cellular mechanisms, signaling pathways, and potential therapeutic targets. By highlighting the critical roles of these pathways and therapies, this review offers valuable insights to inform the development of preventative and therapeutic strategies and to guide future research efforts aimed at addressing this life-threatening condition.

Regulatory T cells (Tregs) are a suppressive CD4+ T cell population that limit the antitumor immune response. In this study, we analyzed the chromatin accessibility of Tregs in the murine tumor microenvironment (TME) to identify tumor-specific accessible peaks and if these are altered over time in the tumor microenvironment, with or without anti-PD-1 immunotherapy. We found that despite little change in chromatin accessibility of Tregs in the tumor over time, Tregs have a distinct chromatin accessibility signature in the TME compared with Tregs in the periphery. This distinct tumor Treg chromatin accessibility profile highlights reduced accessibility at loci important for an CD4+ conventional T cell (CD4+ Foxp3-) effector phenotype. Analysis of chromatin accessibility in Tregs from B16 and MC38 tumor models indicated that Tregs from skin-resident tumors are most similar to naïve skin resident Tregs but still bear key differences attributable to the TME. We also found that Tregs do not alter their transcriptome or chromatin accessibility following immunotherapy. We conclude that although chromatin accessibility in Tregs is somewhat similar to their tissue residency, the TME may drive a unique chromatin accessibility profile. Treg chromatin accessibility in the tumor appears remarkably stable and unaltered by tumor type, over time, or following immunotherapy.

Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.

Type 1 diabetes (T1D) is an autoimmune disorder in which pancreatic β-cells are destroyed by CD8+ T cells. Anti-CD3 antibody effectively treats early-stage T1D when β-cell autoantibodies are detected but before symptoms appear. However, it impairs the immune system temporarily, exposing individuals to infection. A therapeutic that can reverse new-onset T1D without harming the immune system remains urgently needed. Herein, we have constructed cellular vesicles presenting granzyme B-responsive fusion proteins (designated aCD8-GrzBcs-IL2) composed of a single-chain variable fragment of anti-CD8 antibodies and a mutein interleukin-2 (IL2). aCD8-GrzBcs-IL2 is designed to simultaneously inhibit CD8+ T cells and promote Treg cells, especially when CD8+ T cells are attacking β-cells. In vitro, these cellular vesicles can inhibit the cell-killing effect of CD8+ T cells and enhance the expansion of Treg cells. Notably, intravenous administration of aCD8-GrzBcs-IL2-expressed cellular vesicles reversed newly onset diabetes in 77.8% of nonobese diabetic (NOD) mice without reducing blood CD3+ T cells and CD8+ T cells, indicating a favorable safety profile.

Diffuse hemispheric glioma (DHG), H3 G34-mutant, representing 9-15% of cases, are aggressive Central Nervous System (CNS) tumors with poor prognosis. This study examines the role of epigenetic reprogramming of the immune microenvironment and the response to immune-mediated therapies in G34-mutant DHG. To this end, we utilized human G34-mutant DHG biopsies, primary G34-mutant DHG cultures, and genetically engineered G34-mutant mouse models (GEMMs). Our findings show that the G34 mutation alters histone marks' deposition at promoter and enhancer regions, leading to the activation of the JAK/STAT pathway, which in turn results in an immune-permissive tumor microenvironment. The implementation of Ad-TK/Ad-Flt3L immunostimulatory gene therapy significantly improved median survival, and lead to over 50% long term survivors. Upon tumor rechallenge in the contralateral hemisphere without any additional treatment, the long-term survivors exhibited robust anti-tumor immunity and immunological memory. These results indicate that immune-mediated therapies hold significant potential for clinical translation in treating patients harboring H3.3-G34 mutant DHGs, offering a promising strategy for improving outcomes in this challenging cancer subtype affecting adolescents and young adults (AYA).

This study uncovers the role of the H3.3-G34 mutation in reprogramming the tumor immune microenvironment in diffuse hemispheric gliomas. Our findings support the implementation of precision medicine informed immunotherapies, aiming at improving enhanced therapeutic outcomes in adolescents and young adults harboring H3.3-G34 mutant DHGs.

Autoimmune diseases result from imbalances in the immune system and disturbances in the mechanisms of immune tolerance. T-regulatory cells (Treg) are key factors in the formation of immune tolerance. Tregs modulate immune responses and repair processes, controlling the innate and adaptive immune system. The use of Tregs in the treatment of autoimmune diseases began with the manipulation of endogenous Tregs using immunomodulatory drugs. Then, a method of adoptive transfer of Tregs grown in vitro was developed. Adoptive transfer of Tregs includes polyclonal Tregs with non-specific effects and antigen-specific Tregs in the form of CAR-Treg and TCR-Treg. This review discusses non-specific and antigen-specific approaches to the use of Tregs, their advantages, disadvantages, gaps in development, and future prospects.

Antigen-specific therapies have a long history in the treatment of allergy but have not been successful in autoimmunity. However, in the past 20 years, advances in the definition of the self-antigens that promote autoimmunity and the growing understanding of the mechanisms that maintain tolerance in health but fail in autoimmunity have led to antigen-specific approaches being considered for the treatment of autoimmune diseases. The core goal of each antigen-specific treatment approach is to remove the immune response that promotes autoimmunity whilst sparing protective responses. Approaches to antigen-specific therapy range from targeted deletion of autoreactive lymphocytes to tolerization of autoreactive T cells and active inhibition of autoimmune responses. Technologies such as vaccines, nanoparticles, cell-based therapies and gene editing are being harnessed to achieve these goals. Remaining challenges include the selection of the best antigen to target, modality and timing of administration of these therapies and the disease in which the therapies are used; overcoming these challenges will be vital to move antigen-specific therapies forward. Once established, antigen-specific therapy has the potential to be applied broadly in the area of autoimmunity.

Multiple Sclerosis (MS) is an autoimmune condition targeting the central nervous system (CNS) characterized by focal demyelination with inflammation, causing neurodegeneration and gliosis. This is accompanied by a refractory period in relapsing MS or chronic progression in primary progressive MS. Current MS treatments target disease relapses and aim to reduce further demyelination and disability. These include the treatment of acute exacerbations through global immunomodulation upon corticosteroid administration, which are accompanied by adverse reactions. Disease modifying therapies (DMTs) which provide targeted immunosuppression of T and B cells, and sequestration of leukocytes out of CNS, have led to further improvements in demyelination prevention and disease burden reduction. Despite their efficacy, DMTs are ineffective in remyelination, pathology reversal and have minimal effects in progressive MS. The advent of modern biomedical engineering approaches in combination with a better understanding of MS pathology, has led to the development of novel, regenerative approaches to treatment. Such treatments utilize neural stem cells (NSCs) and can reduce disease relapses and reverse damage caused by the disease through localized tissue regeneration. While at initial stages, pre-clinical and clinical studies utilizing NSCs and immune modulation have shown promising outcomes in tissue regeneration, creating a potential new era in MS therapy.

Glutamine, akin to glucose, is a fundamental nutrient for human physiology. Tumor progression is often accompanied by elevated glutamine consumption, resulting in a disrupted nutritional balance and metabolic reprogramming within the tumor microenvironment. Furthermore, immune cells, which depend on glutamine for metabolic support, may experience functional impairments and dysregulation. Although the role of glutamine in tumors has been extensively studied, the specific impact of glutamine competition on immune responses, as well as the precise cellular alterations within immune cells, remains incompletely understood. In this review, we summarize the consequences of glutamine deprivation induced by tumor-driven glutamine uptake on immune cells, assessing the underlying mechanisms from the perspective of various components of the immune microenvironment. Additionally, we discuss the potential synergistic effects of glutamine supplementation and immunotherapy, offering insights into future research directions. This review provides compelling evidence for the integration of glutamine metabolism and immunotherapy as a promising strategy in cancer therapy.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and facilitating tissue regeneration by fostering an environment conducive to tissue repair. However, in damaged tissues, excessive inflammatory responses can overwhelm the immunomodulatory capacity of Tregs, compromising their functionality and potentially hindering effective regeneration. Mesenchymal stem cells (MSCs) play a key role in enhancing Treg function. MSCs enhance Treg activity through indirect interactions, such as cytokine secretion, and direct interactions via membrane proteins.

This review examines the regenerative functions of Tregs across various tissues, including bone, cartilage, muscle, and skin, and explores strategies to enhance Treg functionality using MSCs. Advanced techniques, such as the overexpression of relevant genes in MSCs, are highlighted for their potential to further enhance Treg function. Additionally, emerging technologies utilizing extracellular vesicles (EVs) and cell membrane-derived vesicles derived from MSCs offer promising alternatives to circumvent the potential side effects associated with live cell therapies. This review proposes approaches to enhance Treg function and promote tissue regeneration and also outlines future research directions.

This review elucidates recent technological advancements aimed at enhancing Treg function using MSCs and examines their potential to improve tissue regeneration efficiency.

The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.

Aneurysmal subarachnoid hemorrhage (SAH) involves a significant influx of blood into the cerebrospinal fluid, representing a severe form of stroke. Despite advancements in aneurysm closure and neuro-intensive care, outcomes remain impaired due to cerebral vasospasm and delayed cerebral ischemia (DCI). Previous pharmacological therapies have not successfully reduced DCI while improving overall outcomes. As a result, significant efforts are underway to better understand the cellular and molecular mechanisms involved. This review focuses on the activation and effects of immune cells after SAH and their interactions with neurotoxic and vasoactive substances as well as inflammatory mediators. Particular attention is given to clinical studies highlighting the roles of natural killer (NK) cells and regulatory T cells (Treg) cells. Alongside microglia, astrocytes, and oligodendrocytes, NK cells and Treg cells are key contributors to the inflammatory cascade following SAH. Their involvement in modulating the neuro-inflammatory response, vasospasm, and DCI underscores their potential as therapeutic targets and prognostic markers in the post-SAH recovery process. We conducted a systematic review on T cell- and natural killer cell-mediated inflammation and their roles in cerebral vasospasm and delayed cerebral ischemia. We conducted a meta-analysis to evaluate outcomes and mortality in studies focused on NK cell- and T cell-mediated mechanisms.

Lim and colleagues demonstrate that synNotch transcriptional circuits engineered into T cells can be used to precisely control location-specific expression of payloads responding to antigen triggers, thus locally inhibiting unwanted immunity or neuroinflammation. With no off-tumor toxicity or systemic immunosuppression upon elimination of mouse brain tumors, this approach can achieve better efficacy than anticipated.

Regulatory T (Treg) cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases, such as autoimmune diseases, graft-versus-host disease (GVHD), tumors, and infectious diseases. Treg cells exert suppressive function via distinct mechanisms, including inhibitory cytokines, granzyme or perforin-mediated cytolysis, metabolic disruption, and suppression of dendritic cells. Forkhead Box P3 (FOXP3), the characteristic transcription factor, is essential for Treg cell function and plasticity. Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications (PTMs), including ubiquitination, acetylation, phosphorylation, methylation, glycosylation, poly(ADP-ribosyl)ation, and uncharacterized modifications. This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function. Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases, GVHD, tumors, and infectious diseases.

Cardiometabolic and cardiovascular diseases (CVDs) remain the leading cause of death worldwide, with well-established risk factors such as smoking, obesity, and diabetes contributing to plaque formation and chronic inflammation. However, emerging evidence suggests that the immune system plays a more significant role in the development and progression of CVD than previously thought. Specifically, the finely tuned regulation of lymphocyte subsets governs post-injury inflammation and tissue damage resolution and orchestrates the functions and activation of endothelial cells, cardiomyocytes, and fibroblasts in CVD-associated lesions (e.g., atherosclerotic plaques). A deeper understanding of the immune system's involvement in CVD development and progression will provide new insights into disease biology and uncover novel therapeutic targets aimed at re-establishing immune homeostasis. In this review, we summarize the current state of knowledge on the distribution and involvement of lymphocyte subsets in CVD, including atherosclerosis, diabetes, hypertension, myocardial infarction, and stroke.