Chimeric antigen receptor T cells recognizing CD19 (19CAR-T) cell therapy has achieved robust clinical efficacy when treating some hematological malignancies, but which patient subgroups benefit mostly remains elusive. Here we summarized the data of 541 patients from 30 clinical trials who underwent 19 CAR-T therapy and analyzed the different clinical responses between young (<44 years), middle-aged (45-59 years) and elderly (>60 years) patients and found that the young patients showed a higher level of complete response (CR) rate. Therefore, we then summarize the advances of studies focusing on the effects of age on anti-tumor efficacy of CAR-T therapy and analyze the reasons for the low CR rate after CAR-T cell therapy in elderly patients with tumors, aiming to provide hints for oncologists to select the most suitable candidate for this cancer immunotherapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune interactions. Elucidating the causal relationships between blood cell perturbations, immune cell subsets, and RA can provide valuable insights into its pathogenesis.

This study employed bidirectional two-sample Mendelian Randomization (MR) to explore the causal effects of blood cell perturbations on RA risk, with a focus on immune cell mediation. Genetic data from large-scale Genome-Wide Association Studies (GWAS) were utilized to select instrumental variables (IVs) for exposure, mediator, and outcome. Inverse Variance Weighted (IVW) analysis was applied, supplemented by sensitivity tests. Mediation analysis was conducted to assess the indirect effects mediated by immune cells.

Significant causal associations were identified between perturbations in reticulocytes, monocytes, and lymphocytes and specific immune cell subsets, including CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + terminally differentiated CD8 + T cells (CD45RA + TD CD8 + cells). Erythropoiesis perturbation was associated with a reduced RA risk, while perturbations in monocytes and lymphocytes were found to facilitate RA progression through immune-mediated mechanisms.

This study underscores the pivotal role of immune cell subsets in mediating the effects of blood cell perturbations on RA development. These findings suggest that targeting immune cell-mediated pathways, particularly those involving Tregs and CD8 + T cells, can provide new therapeutic strategies for RA management. Key Points • Causal Relationships: Mendelian randomization (MR) analysis identified significant causal relationships between specific blood cell disturbances (e.g., reticulocytes, monocytes, and lymphocytes) and rheumatoid arthritis (RA). • Role of Immune Cells: CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + Terminally Differentiated CD8 + T cells (CD45RA + TD CD8 + cells) mediate the association between blood cell disturbances and RA. • Protective Role of Reticulocytes: Reticulocyte disturbances under potassium chloride (KCl) conditions are negatively associated with RA, potentially protecting joints from inflammatory damage by reducing oxidative stress. • Protective Role of Non-Classical Monocytes: Baseline disturbances in monocyte median side scatter are negatively associated with RA, suggesting non-classical monocytes may reduce RA-related inflammation. • Positive Association of Lymphocyte Disturbances with RA: Lymphocyte side scatter standard deviation under colchicine disturbances shows a significant positive association with RA, indicating abnormal T cell activation may exacerbate RA progression.AQ.

Diabetic retinopathy features damage to the retinal microvasculature that causes vessels to leak and proliferate and can lead to vision loss and blindness. Inflammation contributes to the development of diabetic retinopathy, but little is known about the role of the adaptive immune system, including the benefits of augmenting the Forkhead box protein P3 (Foxp3) regulatory T cell (Treg) compartment. We aimed to determine whether treatment with low-dose IL-2 expands and activates Tregs and reduces CD8+ T cells in the retina, and attenuates retinal inflammation and vasculopathy in murine models of diabetic retinopathy and neovascular retinopathy.

Mouse models of streptozocin-induced diabetes and oxygen-induced retinopathy (OIR) were administered low-dose IL-2 (25,000 U) or vehicle (sterile water) by i.p. injection. Reporter mice expressing Foxp3 as a red fluorescent protein (RFP) conjugate or CD8 as a green fluorescent protein (GFP) conjugate were used to evaluate Foxp3+ Tregs and CD8+ T cells, respectively, in blood, lymphoid organs and retina using flow cytometry or confocal microscopy. Vasculopathy and the expression of angiogenic and inflammatory factors were assessed in the retina.

Low-dose IL-2 significantly expanded CD4+CD25+Foxp3+ Tregs in the blood and spleen of mouse models of OIR and diabetes (1.4- to 1.9-fold increase, p<0.01). This expansion enhanced Treg functionality, increasing the expression of cytotoxic T-lymphocyte-associated protein4 (CTLA4), programmed cell death protein1 (PD1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), and increased the ratio of Tregs to CD8+ T cells. This was accompanied in the retina by a twofold increase in Foxp3+ Tregs (diabetes: 3.01 ± 0.41 vs 5.90 ± 1.25 cells per field, p<0.001; OIR: 4.41 ± 1.48 vs 10.05 ± 2.91 cells per field, p<0.001) and a reduction in CD8+ T cells (diabetes: 4.65 ± 0.58 vs 3.00 ± 0.81 cells per field, p<0.01; OIR: 5.51 ± 1.33 vs 3.17 ± 1.14 cells per field, p<0.01). Low-dose IL-2 reduced the levels of the potent inflammatory factors intercellular adhesion protein1 and TNF and the chemokine IFNγ-inducible protein10 (IP-10) in the retina. Importantly, low-dose IL-2 treatment effectively attenuated retinal vasculopathy, with marked reductions in acellular capillaries (diabetes: 0.48-fold decrease, p<0.001), neovascularisation (OIR: 0.68-fold decrease, p<0.01) and vascular leakage, and expression of vascular endothelial growth factor.

This study highlights the therapeutic potential of low-dose IL-2 to reduce retinal inflammation and severe vascular injury by boosting Tregs and reducing CD8+ T cells and inflammatory factors.

It is increasingly appreciated that the expression of immunoregulatory molecules within tumors have potential to shape a microenvironment that promotes local immunoevasion and immunoregulation. However, little is known about tissue-intrinsic immunomodulatory mechanisms following transplantation. We propose that differences in the phenotype of microvascular endothelial cells impact the alloantigenicity of the graft and its potential to promote immunoregulation following transplantation. We focus this review on the concept that graft-dependent immunoregulation may evolve post-transplantation, and that it is dependent on the phenotype of select subsets of intragraft endothelial cells. We also discuss evidence that long-term graft survival is critically dependent on adaptive interactions among immune cells and endothelial cells within the transplanted tissue microenvironment.

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.

The primary source of short-chain fatty acids (SCFAs), now recognized as critical mediators of host health, particularly in the context of neurobiology and cancer development, is the gut microbiota's fermentation of dietary fibers. Recent research highlights the complex influence of SCFAs, such as acetate, propionate, and butyrate, on brain cancer progression. These SCFAs impact immune modulation and the tumor microenvironment, particularly in brain tumors like glioma. They play a critical role in regulating cellular processes, including apoptosis, cell differentiation, and inflammation. Moreover, studies have linked SCFAs to maintaining the integrity of the blood-brain barrier (BBB), suggesting a protective role in preventing tumor infiltration and enhancing anti-tumor immunity. As our understanding of the gut-brain axis deepens, it becomes increasingly important to investigate SCFAs' therapeutic potential in brain cancer management. Looking into how SCFAs affect brain tumor cells and the environment around them could lead to new ways to prevent and treat these diseases, which could lead to better outcomes for people who are dealing with these challenging cancers.

The oral epithelium, a dynamic interface constantly facing environmental challenges, relies on intricate molecular pathways to maintain its homeostasis. This comprehensive review delves into the nuanced interplay between T-lymphocytic cells (T cells) and RNA-binding proteins (RBPs) within the oral epithelium, elucidating their roles in orchestrating immune responses and influencing tissue plasticity. By synthesizing current knowledge, we aim to unravel the molecular intricacies that govern this interplay, with a focus on potential therapeutic implications for oral health and diseases. Understanding the regulatory networks shaped by T cells and RBPs in the oral epithelial microenvironment holds promise for innovative strategies in managing conditions associated with epithelial dysfunction.

Intracerebral hemorrhage (ICH) is a common cerebrovascular disease that can lead to severe neurological dysfunction in surviving patients, resulting in a heavy burden on patients and their families. When ICH occurs, the blood‒brain barrier is disrupted, thereby promoting immune cell migration into damaged brain tissue. As important immunosuppressive T cells, regulatory T (Treg) cells are involved in the maintenance of immune homeostasis and the suppression of immune responses after ICH. Treg cells mitigate brain tissue damage after ICH in a variety of ways, such as inhibiting the neuroinflammatory response, protecting against blood‒brain barrier damage, reducing oxidative stress damage and promoting nerve repair. In this review, we discuss the changes in Treg cells in ICH clinical patients and experimental animals, the mechanisms by which Treg cells regulate ICH and treatments targeting Treg cells in ICH, aiming to support new therapeutic strategies for clinical treatment.

G protein-coupled receptor 55 (GPR55) is a lipid-sensing receptor that plays a role as an immune mediator and is primarily upregulated during immune cell activation. There is a lack of knowledge about the role of GPR55 in allergic inflammatory diseases such as atopic dermatitis. The purpose of this study was to investigate the role of GPR55 through the use of its antagonist, CID16020046, in an atopic dermatitis mouse model. It was found that BALB/c mice develop lesions similar to those associated with atopic dermatitis following sensitization and repeated exposure to 1-chloro-2,4-dinitrobenzene (DNCB). It was found that CID16020046 (1 mg/kg, i. p.) alleviated the atopic dermatitis-like symptoms as well as immune dysregulation caused by DNCB. Based on histopathological analysis, CID16020046 reduced ear thickening and mast cell counts in the dermis. CID16020046 decreased DNCB-induced increases in serum IgE levels, as measured using enzyme-linked immunosorbent assays. A significant reduction in lymph node hypertrophy was also observed with CID16020046 as well as significant reductions in CD4+ T helper 1 (Th1), Th2, and Th17 cells in the lymph nodes. As a result of the administration of CID16020046, cytokines of Th1 (IFN-γ), Th2 (IL-4 and IL-13), and Th17 (IL-17 A) types were also reduced in the skin and lymph nodes. In conclusion, blocking GPR55 alleviates DNCB-induced atopic dermatitis-like symptoms, suggesting that GPR55 is a potential therapeutic target for allergic inflammatory diseases via immunoregulation.

Targeted immunotherapies make substantial strides in clinical cancer care due to their ability to counteract the tumor's capacity to suppress immune responses. Advances in biomimetic technology with minimally immunogenic and highly targeted, are addressing issues of targeted drug delivery and disrupting the tumor's immunosuppressive environment to trigger immune activation. Specifically, the use of dendritic cell (DC) membranes to coat nanoparticles ensures targeted delivery due to DC's unique ability to activate naive T cells, spotlighting their role in immunotherapy aimed at disrupting the tumor microenvironment. The potential of DC's biomimetic membrane to mediate immune activation and target tumors is gaining momentum, enhancing the effectiveness of cancer treatments in conjunction with other immune responses. This review delves into the methodologies behind crafting DC membranes and the fusion of dendritic and tumor cell membranes for encapsulating therapeutic nanoparticles. It explores their applications and recent advancements in combating cancer, offering an all-encompassing perspective on DC biomimetic nanosystems, immunotherapy driven by antigen presentation, and the collaborative efforts of drug delivery in chemotherapy and photodynamic therapies. Current evidence shows promise in augmenting combined therapeutic approaches for cancer treatment and holds translational potential for various cancer treatments in a clinical setting.

Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2n Treg-KO ) of adult mice results in a robust expansion and activation of cytotoxic CD8 + T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.

In the present review, we focused on recent translational and clinical discoveries in asthma immunology, facilitating phenotyping and stratified or personalized interventions for patients with this condition. The immune processes behind chronic inflammation in asthma exhibit marked heterogeneity, with diverse phenotypes defining discernible features and endotypes illuminating the underlying molecular mechanisms. In particular, two primary endotypes of asthma have been identified: "type 2-high," characterized by increased eosinophil levels in the airways and sputum of patients, and "type 2-low," distinguished by increased neutrophils or a pauci-granulocytic profile. Our review encompasses significant advances in both innate and adaptive immunities, with emphasis on the key cellular and molecular mediators, and delves into innovative biological and targeted therapies for all the asthma endotypes. Recognizing that the immunopathology of asthma is dynamic and continuous, exhibiting spatial and temporal variabilities, is the central theme of this review. This complexity is underscored through the innumerable interactions involved, rather than being driven by a single predominant factor. Integrated efforts to improve our understanding of the pathophysiological characteristics of asthma indicate a trend toward an approach based on disease biology, encompassing the combined examination of the clinical, cellular, and molecular dimensions of the disease to more accurately correlate clinical traits with specific disease mechanisms.

Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to "humanize" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the "microbiota" and "gut lymphocyte homing" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013-1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012-1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835-0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864-0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630-0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001-1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system resulting from loss of immune tolerance. Many disease-modifying therapies for MS have broad immunosuppressive effects on peripheral immune cells, but this can increase risks of infection and attenuate vaccine-elicited immunity. A more targeted approach is to re-establish immune tolerance in an autoantigen-specific manner. This review discusses methods to achieve this, focusing on tolerogenic dendritic cells. Clinical trials in other autoimmune diseases also provide learnings with regards to clinical translation of this approach, including identification of autoantigen(s), selection of appropriate patients and administration route and frequency.

Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.

Tregs have the potential to establish long-term immune tolerance in patients recently diagnosed with type 1 diabetes (T1D) by preserving β cell function. Adoptive transfer of autologous thymic Tregs, although safe, exhibited limited efficacy in previous T1D clinical trials, likely reflecting a lack of tissue specificity, limited IL-2 signaling support, and in vivo plasticity of Tregs. Here, we report a cell engineering strategy using bulk CD4+ T cells to generate a Treg cell therapy (GNTI-122) that stably expresses FOXP3, targets the pancreas and draining lymph nodes, and incorporates a chemically inducible signaling complex (CISC). GNTI-122 cells maintained an expression profile consistent with Treg phenotype and function. Activation of CISC using rapamycin mediated concentration-dependent STAT5 phosphorylation and, in concert with T cell receptor engagement, promoted cell proliferation. In response to the cognate antigen, GNTI-122 exhibited direct and bystander suppression of polyclonal, islet-specific effector T cells from patients with T1D. In an adoptive transfer mouse model of T1D, a mouse engineered-Treg analog of GNTI-122 trafficked to the pancreas, decreased the severity of insulitis, and prevented progression to diabetes. Taken together, these findings demonstrate in vitro and in vivo activity and support further development of GNTI-122 as a potential treatment for T1D.

Myocardial ischemia-reperfusion injury (MIRI) is closely related to the final infarct size in acute myocardial infarction (AMI). Therefore, reducing MIRI can effectively improve the prognosis of AMI patients. At the same time, the healing process after AMI is closely related to the local inflammatory microenvironment. Regulatory T cells (Tregs) can regulate various physiological and pathological immune inflammatory responses and play an important role in regulating the immune inflammatory response after AMI. However, different subtypes of Tregs have different effects on MIRI, and the same subtype of Tregs may also have different effects at different stages of MIRI. This article systematically reviews the classification and function of Tregs, as well as the role of various subtypes of Tregs in MIRI. A comprehensive understanding of the role of each subtype of Tregs can help design effective methods to control immune reactions, reduce MIRI, and provide new potential therapeutic options for AMI.

RECQL is essential for genomic stability. Here, we evaluated RECQL in 449 pure ductal carcinomas in situ (DCIS), 152 DCIS components of mixed DCIS/invasive breast cancer (IBC) tumors, 157 IBC components of mixed DCIS/IBC and 50 normal epithelial terminal ductal lobular units (TDLUs). In 726 IBCs, CD8+, FOXP3+, IL17+, PDL1+, PD1+ T-cell infiltration (TILs) were investigated in RECQL deficient and proficient cancers. Tumor mutation burden (TMB) was evaluated in five RECQL germ-line mutation carriers with IBC by genome sequencing. Compared with normal epithelial cells, a striking reduction in nuclear RECQL in DCIS was evident with aggressive pathology and poor survival. In RECQL deficient IBCs, CD8+, FOXP3+, IL17+ or PDL1+ TILs were linked with aggressive pathology and shorter survival. In germline RECQL mutation carriers, increased TMB was observed in 4/5 tumors. We conclude that RECQL loss is an early event in breast cancer and promote immune cell infiltration.

A functional immune system is crucial for a healthy life, protecting from infections, tumors, or autoimmune disorders; these are accomplished by the interaction between various immune cells. Nourishment, particularly micronutrients, are very important components in the immune system balance, therefore this review emphasizes the vitamins (D, E, A, C) and Dendritic cells' subsets due to vitamins' roles in immune processes, especially on dendritic cells' functions, maturation, and cytokine production. Current studies reveal significant benefits related to vitamins, including vitamin E, which can contribute to the control of dendritic cells' function and maturation. Furthermore, vitamin D plays an immunoregulatory and anti-inflammatory role in the immune system. Metabolite of vitamin A which is called retinoic acid leads to T cells' differentiation to T helper 1 or T helper 17, so low levels of this vitamin exacerbate the menace of infectious diseases, and vitamin C has anti-oxidant effects on dendritic cells and modulate their activation and differentiation program. Additionally, the correlation between the amount of vitamin and the occurrence or progression of allergic diseases and autoimmunity disorders is discussed according to the results of previous studies.

Pulmonary fibrosis is a chronic and often fatal disease. The pathogenesis is characterized by aberrant repair of lung parenchyma, resulting in loss of physiological homeostasis, respiratory failure, and death. The immune response in pulmonary fibrosis is dysregulated. The gut microbiome is a key regulator of immunity. The role of the gut microbiome in regulating the pulmonary immunity in lung fibrosis is poorly understood. Here, we determine the impact of gut microbiota on pulmonary fibrosis in substrains of C57BL/6 mice derived from different vendors (C57BL/6J and C57BL/6NCrl). We used germ-free models, fecal microbiota transplantation, and cohousing to transmit gut microbiota. Metagenomic studies of feces established keystone species between substrains. Pulmonary fibrosis was microbiota dependent in C57BL/6 mice. Gut microbiota were distinct by β diversity and α diversity. Mortality and lung fibrosis were attenuated in C57BL/6NCrl mice. Elevated CD4+IL-10+ T cells and lower IL-6 occurred in C57BL/6NCrl mice. Horizontal transmission of microbiota by cohousing attenuated mortality in C57BL/6J mice and promoted a transcriptionally altered pulmonary immunity. Temporal changes in lung and gut microbiota demonstrated that gut microbiota contributed largely to immunological phenotype. Key regulatory gut microbiota contributed to lung fibrosis, generating rationale for human studies.

The nuclear factor of activated T cells (NFAT) was first identified as a transcriptional regulator of activated T cells. The NFAT family is involved in the development of tumors. Furthermore, recent evidence reveals that NFAT proteins regulate the development of inflammatory and immune responses. New discoveries have also been made about the mechanisms by which NFAT regulates cancer progression through cancer stem cells (CSC). Here, we discuss the role of the NFAT family in the immune system and various cancer types.

Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of "health," is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a "leaky gut," permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.

In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D.

To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice.

InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function and expression in the tumor microenvironment make them attractive targets for immunotherapy, leading to the development of IL-2/IL-2R-targeted therapeutic strategies. However, the dynamic interplay between IL-2/IL-2R and various immune cells and their dual roles in promoting immune activation and tolerance presents a complex landscape for clinical exploitation. This review discusses the pivotal roles of IL-2 and IL-2R in tumorigenesis, shedding light on their potential as diagnostic and prognostic markers and their therapeutic manipulation in cancer. It underlines the necessity to balance the anti-tumor activity with regulatory T-cell expansion and evaluates strategies such as dose optimization and selective targeting for enhanced therapeutic effectiveness. The article explores recent advancements in the field, including developing genetically engineered IL-2 variants, combining IL-2/IL-2R-targeted therapies with other cancer treatments, and the potential benefits of a multidimensional approach integrating molecular profiling, immunological analyses, and clinical data. The review concludes that a deeper understanding of IL-2/IL-2R interactions within the tumor microenvironment is crucial for realizing the full potential of IL-2-based therapies, heralding the promise of improved outcomes for cancer patients.

Recent studies on genetically susceptible individuals and animal models revealed the potential role of the intestinal microbiota in the pathogenesis of type 1 diabetes (T1D) through complex interactions with the immune system. T1D incidence has been increasing exponentially with modern lifestyle altering normal microbiota composition, causing dysbiosis characterized by an imbalance in the gut microbial community. Dysbiosis has been suggested to be a potential contributing factor in T1D. Moreover, several studies have shown the potential role of probiotics in regulating T1D through various mechanisms. Current T1D therapies target curative measures; however, preventive therapeutics are yet to be proven. This review highlights immune microbiota interaction and the immense role of probiotics and postbiotics as important immunological interventions for reducing the risk of T1D.

Regulatory T cells (Tregs) control immune responses and are essential to maintain immune homeostasis and self-tolerance. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs. These diseases have currently no cure and are treated with palliative drugs such as immunosuppressant and immunomodulatory agents. Thereby, there is a great interest in developing medical interventions against these diseases based on enhancing Treg cell function and numbers. Here, we give an overview of Treg cell ontogeny and function, paying particular attention to mucosal Tregs. We review some notable approaches to enhance immunomodulation by Tregs with therapeutic purposes including adoptive Treg cell transfer therapy and discuss relevant clinical trials for inflammatory bowel disease. We next introduce ways to expand mucosal Tregs in vivo using microbiota and dietary products that have been the focus of clinical trials in various autoimmune and chronic-inflammatory diseases.

This review addresses recent progress in our understanding of the role of regulatory T (Treg) cells in enforcing immune tolerance and tissue homeostasis in the lung at steady state and in directing the immune response in asthmatic lung inflammation.

Regulatory T cells regulate the innate and adaptive immune responses at steady state to enforce immune tolerance in lung tissues at steady state and their control of the allergic inflammatory responses induced by allergens. This regulatory function can break down in the context of chronic asthmatic airway inflammation such that the lung tissue Treg cells become skewed towards a pathogenic phenotype that aggravates and perpetuates disease. Subversion of lung tissue Treg cell function involves their upregulation of Notch4 expression, which in turn acts to amplify T helper type 2 and type 17 and innate lymphoid cell type 2 responses in the airways.

A dual role for Treg cells has emerged both as immune regulators but also a potential disease effectors in asthma, with implications for disease therapy.

Severe cases of COVID-19 present hyperinflammatory condition that can be fatal. Little is known about the role of regulatory responses in SARS-CoV-2 infection. In this study, we evaluated the phenotype of regulatory T cells in the blood (peripheral blood mononuclear cell) and the lungs (broncho-alveolar) of adult patients with severe COVID-19 under invasive mechanical ventilation. Our results show important dynamic variation on Treg cells phenotype during COVID-19 with changes in number and functional parameters from the day of intubation (Day 1 of intensive care unit admission) to Day 7. We observed that compared with surviving patients, non-survivors presented lower numbers of Treg cells in the blood. In addition, lung Tregs of non-survivors also displayed higher PD1 and lower FOXP3 expressions suggesting dysfunctional phenotype. Further signs of Treg dysregulation were observed in non-survivors such as limited production of IL-10 in the lungs and higher production of IL-17A in the blood and in the lungs, which were associated with increased PD1 expression. These findings were also associated with lower pulmonary levels of Treg-stimulating factors like TNF and IL-2. Tregs in the blood and lungs are profoundly dysfunctional in non-surviving COVID-19 patients.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, following strokes and cardiovascular diseases. Chronic lung inflammation is believed to play a role in the development of COPD. In addition, accumulating evidence shows that the immune system plays a crucial role in the pathogenesis of COPD. Significant advancements have been made in research on the pathogenesis of immune diseases and chronic inflammation in recent years, and T helper 17 (Th17) cells and regulatory T (Treg) cells have been found to play a crucial role in the autoimmune response. Th17 cells are a proinflammatory subpopulation that causes autoimmune disease and tissue damage. Treg cells, on the other hand, have a negative effect but can contribute to the occurrence of the same disease when their antagonism fails. This review mainly summarizes the biological characteristics of Th17 cells and Treg cells, their roles in chronic inflammatory diseases of COPD, and the role of the Th17/Treg ratio in the onset, development, and outcome of inflammatory disorders, as well as recent advancements in immunomodulatory treatment targeting Th17/Treg cells in COPD.

Gastric cancer (GC) remains one of the most common malignancies worldwide. Despite immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment and obtained durable clinical responses, only a fraction of GC patients benefit from it. As an important component of T cells, regulatory T cells (Tregs) play a vital role in the pathogenesis of GC, keep a core balance between immune suppression and autoimmunity, and function as predictive biomarkers for prognosis of GC patients. In this review, we discuss the role of Tregs in the pathogenesis of GC, and targeting Tregs via influencing their transcription factor, migration, co-stimulatory receptors, immune checkpoints, and cytokines. We also focus on the currently important findings of Tregs metabolism including amino acid, fatty acid, and lactic acid metabolism of GC. The emerging role of microbiome and clinical combined therapy in modulating Tregs in GC treatment is also summarized. Meanwhile, this review recapitulates a novel regulator, magnesium, is involved in mediating Tregs in GC. These research advances on Treg-related strategies provide new insights and challenges for GC progression, treatment, and prognosis. And we hope our review can stimulate further discovery and implication of mediators and pathways targeting Tregs.

Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teffs). However, molecular mechanisms that enforce Treg-mediated suppression in CD4 Teff are unclear. We found that Tregs suppressed activation-induced global protein synthesis in CD4 Teffs prior to cell division. We analyzed genome-wide changes in the transcriptome and translatome of activated CD4 Teffs. We show that mRNAs encoding for the protein synthesis machinery are regulated at the level of translation in activated CD4 Teffs by Tregs. Tregs suppressed global protein synthesis of CD4 Teffs by specifically inhibiting mRNAs of the translation machinery at the level of mTORC1-mediated translation control through concerted action of immunosuppressive cytokines IL-10 and TGFβ. Lastly, we found that the therapeutic targeting of protein synthesis with the RNA helicase eIF4A inhibitor rocaglamide A can alleviate inflammatory CD4 Teff activation caused by acute Treg depletion in vivo. These data show that peripheral tolerance is enforced by Tregs through mRNA translational control in CD4 Teffs.

Novel biologics are currently being tested in clinical trials for the treatment of autoimmune diseases and the prevention of transplant allograft rejection. Their premise is to deliver highly efficient immunosuppression while minimizing side-effects, as they specifically target inflammatory mediators involved in the dysregulation of the immune system. However, the pleiotropism of soluble mediators and cell-to-cell interactions with potential to exert both proinflammatory and regulatory influences on the outcome of the immune response can lead to unpredictable results. Predicting responses to biologic drugs requires mechanistic understanding of the cell type-specific effect of immune mediators. Elucidation of the central role of regulatory T cells (Treg), a small subset of T cells dedicated to immune homeostasis, in preventing the development of auto- and allo-immunity has provided a deeper understanding of the signaling pathways that govern immune tolerance. This review focuses on the requisite signals that promote Treg homeostasis and discusses the anticipated outcomes of biologics targeting these signals. Our goal is to inform and facilitate the design of cell-specific biologics that thwart T effector cells (Teff) while promoting Treg function for the treatment of autoimmune diseases and the prevention of transplant rejection.

Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response' stable levels of maintenance immunosupression are required. However' the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.

Autoimmune diseases are caused when immune cells act against self-protein. This biological self-non-self-discrimination phenomenon is controlled by a distinct group of lymphocytes known as regulatory T cells (Tregs), which are key inflammatory response regulators and play a pivotal role in immune tolerance and homeostasis. Treg-mediated robust immunosuppression provides self-tolerance and protection against autoimmune diseases. However, once this system fails to operate or poorly operate, it leads to an extreme situation where immune system reacts against self-antigens and destroys host organs, thus causing autoimmune diseases. Tregs can target both innate and adaptive immunity via modulating multiple immune cells such as neutrophils, monocytes, antigen-presenting cells, B cells, and T cells. This review highlights the Treg-mediated immunosuppression, role of several markers and their interplay during Treg development and differentiation, and advances in therapeutic aspects of Treg cells to reduce severity of autoimmunity-related conditions along with emphasizing limitations and challenges of their usages.

The principal goal of the study was to verify the concept of pharmacological induction of Foxp3⁺CD25⁺CD4⁺ T regulatory (Treg) cells which will additionally be characterized by a highly suppressive phenotype, i.e., by extensive CD25 and CD39 expression and IL-10 and TGF-β production. Stimulated and unstimulated murine lymphocytes were exposed to IL-27, teriflunomide (TER), and all trans retinoic acid (ATRA) alone and to their combinations. The study demonstrated that: (a) IL-27 alone induced CD39 expression on Treg cells and the generation of Tr1 cells; (b) TER alone induced Foxp3-expressing CD4⁺ T cells and up-regulated density of CD25 on these cells; TER also induced the ability of Treg cells to TGF-β production; (c) ATRA alone induced CD39 expression on Treg cells. The experiments revealed a strong superadditive effect between IL-27 and ATRA with respect to increasing CD39 expression on Treg cells. Moreover, IL-27 and ATRA in combination, but not alone, induced the ability of Treg cells to IL-10 production. However, the combination of IL-27, TER, and ATRA did not induce the generation of Treg cell subset with all described above features. This was due to the fact that TER abolished all listed above desired effects induced by IL-27 alone, ATRA alone, and their combination. IL-27 alone, ATRA alone, and their combination affected TER-induced effects to a lesser extent. Therefore, it can be concluded that in the aspect of pharmacological induction of Treg cells with a highly suppressive phenotype, the triple combination treatment with TER, IL-27, and ATRA does not provide any benefits over TER alone or dual combination including IL-27 and ATRA.

TNFa blocking agents were the first-in-class biologic drugs used for the treatment of autoimmune disease. Paradoxically, however, exacerbation of autoimmunity was observed in some patients. TNFa is a pleiotropic cytokine that has both proinflammatory and regulatory effects on CD4+ T cells and can influence the adaptive immune response against autoantigens. Here, we critically appraise the literature and discuss the intricacies of TNFa signaling that may explain the controversial findings of previous studies. The pleiotropism of TNFa is based in part on the existence of two biologically active forms of TNFa, soluble and membrane-bound, with different affinities for two distinct TNF receptors, TNFR1 and TNFR2, leading to activation of diverse downstream molecular pathways involved in cell fate decisions and immune function. Distinct membrane expression patterns of TNF receptors by CD4+ T cell subsets and their preferential binding of distinct forms of TNFα produced by a diverse pool of cellular sources during different stages of an immune response are important determinants of the differential outcomes of TNFa-TNF receptor signaling. Targeted manipulation of TNFa-TNF receptor signaling on select CD4+ T cell subsets may offer specific therapeutic interventions to dampen inflammation while fortifying immune regulation for the treatment of autoimmune diseases.

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

Adoptive transfer of regulatory T cells (T_regs) is therapeutic in type 1 diabetes (T1D) mouse models. T_regs that are specific for pancreatic islets are more potent than polyclonal T_regs in preventing disease. However, the frequency of antigen-specific natural T_regs is extremely low, and ex vivo expansion may destabilize T_regs, leading to an effector phenotype. Here, we generated durable, antigen-specific engineered T_regs (EngT_regs) from primary human CD4⁺ T cells by combining FOXP3 homology-directed repair editing and lentiviral T cell receptor (TCR) delivery. Using TCRs derived from clonally expanded CD4⁺ T cells isolated from patients with T1D, we generated islet-specific EngT_regs that suppressed effector T cell (T_eff) proliferation and cytokine production. EngT_regs suppressed T_effs recognizing the same islet antigen in addition to bystander T_effs recognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngT_regs homed to the pancreas and blocked diabetes triggered by islet-specific T_effs or diabetogenic polyclonal T_effs in recipient mice. These data demonstrate the potential of antigen-specific EngT_regs as a targeted therapy for preventing T1D.