Huangqi Si Jun Zi decoction (HSJZ), a modified traditional Chinese medicine formula, is known to enhance immunity. However, its immunomodulatory effects in non-small cell lung cancer (NSCLC) remain poorly understood.

This study aimed to investigate the anti-tumor potential of HSJZ in NSCLC and elucidate its mechanisms of action.

In vitro studies assessed HSJZ cytotoxicity in 4 tumor cell lines and its ability to activate immune cells from NSCLC patients, followed by evaluating the cytotoxicity of these activated immune cells against NSCLC cell lines. An orthotopic lung cancer model in mice evaluated in vivo anti-tumor activity. Flow cytometry, immunohistochemistry, and Western blot analysis were conducted to analyze immune cell populations, cytokine production, and protein expression levels, including Tregs, CD8+ T cells, EZH2, and PI3K/AKT signaling pathways.

While HSJZ alone exhibited no direct cytotoxicity on NSCLC cells in vitro, it significantly enhanced immune cell-mediated killing when co-cultured with patient-derived peripheral blood mononuclear cells (PBMCs), accompanied with increased IFN-γ and TNF-α production. In vivo, HSJZ (1 g/kg) treatment in a murine orthotopic lung cancer model resulted in a 54.2 % reduction in tumor burden, as assessed by IVIS spectrum imaging. Mechanistically, HSJZ suppressed regulatory T cells (Tregs) both in vivo and in vitro, as demonstrated by decreased Treg frequency and downregulation of phosphorylated PI3K/AKT signaling in mice bearing Lewis tumor. Moreover, HSJZ significantly inhibited the expression of EZH2, an epigenetic regulator crucial for Treg differentiation.

These findings provide compelling evidence that HSJZ exerts anti-tumor effects in NSCLC by modulating the immune microenvironment, particularly through the inhibition of Tregs activity, as assessed by in vitro co-culture system, in vivo mouse orthotopic Lewis cancer model, immunohistochemistry, etc. Our results support the potential clinical application of HSJZ as an adjunct therapy for NSCLC patients.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, offering life-saving benefits to tumor patients. However, the utilize of ICI agents is often accompanied by immune-related adverse events (irAEs), among which cardiovascular toxicities have attracted more and more attention. ICI induced cardiovascular toxicities predominantly present as acute myocarditis and chronic atherosclerosis, both of which are driven by excessive immune activation. Reprogramming of T cells and macrophages has been demonstrated as a pivotal factor in the pathogenesis of these complications. Therapeutic strategies targeting glycolysis, fatty acid oxidation, reactive oxygen species (ROS) production and some other key signaling have shown promise in mitigating immune hyperactivation and inflammation. In this review, we explored the intricate mechanisms underlying ICI-induced cardiovascular toxicities and highlighted the protective potential of immune reprogramming. We emphasize the roles of T cell and macrophage reprogramming in the heart and vasculature, showcasing their contributions to both short-term and long-term regulation of cardiovascular health. Ultimately, a deeper understanding of these processes will not only enhance the safety of ICIs but also pave the way for innovative strategies to manage immune-related toxicities in cancers therapy.

TNF receptor-associated factor 2 (TRAF2) plays a crucial role in both physiological and pathological processes. It takes part in the regulation of cell survival and death, tissue regeneration, development, endoplasmic reticulum stress response, autophagy, homeostasis of the epithelial barrier and regulation of adaptive and innate immunity. Initially identified for its interaction with TNF receptor 2 (TNFR2), TRAF2 contains a TRAF domain that enables homo- and hetero-oligomerization, allowing it to interact with multiple receptors and signaling molecules. While best known for mediating TNFR1 and TNFR2 signaling, TRAF2 also modulates other receptor pathways, including MAPK, NF-κB, and Wnt/β-catenin cascades. By regulating NF-κB-inducing kinase (NIK), TRAF2 is a key activator of the alternative NF-κB pathway, linking it to inflammatory diseases, immune dysfunction, and tumorigenesis. In the innate immune system, TRAF2 influences macrophage differentiation, activation, and survival and stimulates natural killer cell cytotoxicity. In the adaptive immune system, it represses effector B- and T-cell activity while sustaining regulatory T-cell function, thus promoting immune suppression. The lack of fine-tuning of TRAF2 activity leads to excessive NF-kB activation, driving chronic inflammation and autoimmunity. Although TRAF2 can act as a tumor suppressor, it is predominantly described as a tumor promoter, as its expression has been correlated with increased metastatic potential and poorer prognosis in several types of cancer. Targeting TRAF2 or TRAF2-dependent signaling pathways might represent a promising anti-cancer therapeutic strategy.

During T cell development, heterogeneous nuclear ribonucleoprotein (hnRNP) L is known to regulate CD4 T helper subset differentiation, the proliferation and migration of thymocytes, as loss of hnRNP L in early T cell development results in a failure of T cells to reach the periphery.

To better understand the role of hnRNP L in modulating peripheral T cell trafficking and function, we analyzed T survival and activation in newly generated CD4Cre x hnRNP LFl/Fl (KO) mice. In vitro and in vivo analyses of CD4 T cell differentiation, T cell proliferation and death post activation were performed.

Our initial study of the steady state profile of the KO mice showed normal migration of T cells from the thymus, but peripheral T cell numbers were reduced. Analysis of TCR-mediated signaling pathways revealed normal early T cell activation. However, T cells lacking hnRNP L had marked defects in their ability to differentiate into T helper cell subsets due to reduced proliferation and increased death. In vivo, using immunization studies, KO CD4 T cells failed to fully differentiate into T follicular helper (Tfh) cells and were unable to support the formation of germinal center B cells. Death of activated hnRNP L KO cells could be reversed by treating the cells with zVAD, a pan-caspase inhibitor. In addition, hnRNP L KO cells failed to upregulate the anti-apoptotic protein Bcl-XL following activation.

These studies suggest that hnRNP L plays an important role in T cell activation and survival. Our studies suggest that hnRNP L plays a critical pro-survival role in activated T cells and that alternative splicing of factors that prevent apoptosis may be an important mechanism by which this is achieved.

Tryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine-2,3-dioxygenase 1 (IDO1), IDO2, and Trp-2,3-dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non-enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.

Oral squamous cell carcinoma (OSCC) is a prevalent oral malignancy, which poses significant health risks with a high mortality rate. Regulatory T cells (Tregs), characterized by their immunosuppressive capabilities, are intricately linked to OSCC progression and patient outcomes. The metabolic reprogramming of Tregs within the OSCC tumor microenvironment (TME) underpins their function, with key pathways such as the tryptophan-kynurenine-aryl hydrocarbon receptor, PI3K-Akt-mTOR and nucleotide metabolism significantly contributing to their suppressive activities. Targeting these metabolic pathways offers a novel therapeutic approach to reduce Treg-mediated immunosuppression and enhance anti-tumor responses. This review explores the metabolic dependencies and pathways that sustain Treg function in OSCC, highlighting key metabolic adaptations such as glycolysis, fatty acid oxidation, amino acid metabolism and PI3K-Akt-mTOR signaling pathway that enable Tregs to thrive in the challenging conditions of the TME. Additionally, the review discusses the influence of the oral microbiome on Treg metabolism and evaluates potential therapeutic strategies targeting these metabolic pathways. Despite the promising potential of these interventions, challenges such as selectivity, toxicity, tumor heterogeneity, and resistance mechanisms remain. The review concludes with perspectives on personalized medicine and integrative approaches, emphasizing the need for continued research to translate these findings into effective clinical applications for OSCC treatment.

T lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7 has previously been implicated in cellular Mg2+ homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished human CD4 T-cell activation and proliferation following TCR mediated stimulation. In both primary human CD4 T cells and CRISPR/Cas-9 engineered Jurkat T cells, loss of TRPM7 led to altered Mg2+ homeostasis, Ca2+ signaling, reduced NFAT translocation, decreased IL-2 secretion and ultimately diminished proliferation and differentiation. While the activation of primary human CD4 T cells was dependent on TRPM7, polarization of naïve CD4 T cells into regulatory T cells (Treg) was not. Taken together, these results highlight TRPM7 as a key protein of cellular Mg2+ homeostasis and CD4 T-cell activation. Its role in lymphocyte activation suggests therapeutic potential for TRPM7 in numerous T-cell mediated diseases.

Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.

Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, ensuring a balanced immune response. Tregs primarily operate in an antigen-specific fashion, facilitated by their distinct distribution within discrete niches. Tregs have been studied extensively, from their point of origin in the thymus origin to their fate in the periphery or organs. Signals received from antigen-presenting cells (APCs) stimulate Tregs to dampen inflammation. Almost all tumors are characterized by a pathological abundance of immune suppression in their microenvironment. Conversely, the lack thereof proves detrimental to immunological disorders. Achieving a balanced expression of Tregs in relation to other immune compartments is important in establishing an effective and adaptable immune tolerance towards cancer cells and autoantigens. In the context of cancer, it is essential to decrease the frequency of Tregs to overcome tumor suppression. A lower survival rate is associated with the presence of excessive exhausted effector immune cells and an increased frequency of regulatory cells. However, when it comes to treating graft rejection and autoimmune diseases, the focus lies on immune tolerance and the transfer of Tregs. Here, we explore the complex mechanisms that Tregs use in human disease to balance effector immune cells.

Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.

Radiotherapy (RT) is a crucial clinical modality for cancer. However, nonselectivity, toxicity to normal tissues, and radio-resistance severely limit RT applications. This study develops a versatile X-ray theranostic nano-antioxidant (XTN) to prevent normal tissues from oxidative damage and induce systematic and robust anticancer immunity. XTN owns NIR-II photoacoustic (PA) imaging properties for precise discrimination of the tumor margin through, thereby improving the accuracy of RT. Additionally, XTN is a nano-antioxidant to enhance the cell viability of normal cells after irradiation. Most importantly, XTN scavenges reactive oxygen species (ROS) in the TME to preserve the stimulatory activity of released high mobility group protein B1 to dendritic cells (DCs) and recover T cells' immune function. Meanwhile, XTN achieves charge-reversal specifically releasing an immunomodulator (demethylcantharidin, DMC) in the acidic TME. Moreover, the specifically released DMC inhibits protein phosphatase-2A activity and reduces regulatory T cell (Treg) differentiation. In the bilateral 4T1 tumor model, XTN-mediated radioimmunotherapy remarkably boosts a systemic antitumor immune response and induces durable immunological memory against tumor growth.

The molecular mechanisms that govern differential T cell development from CD4+CD25-conventional T (Tconv) into CD4+CD25+ forkhead-box-P3+ (FoxP3+) inducible regulatory T (iTreg) cells remain unclear. Herein, we investigated the relative contribution of protein kinase A (PKA) in this process. Mechanistically, we found that PKA controlled the efficiency of human iTreg cell generation through the expression of different FoxP3 splicing variants containing or not the exon 2. We found that transient PKA inhibition reduced the recruitment of cAMP-responsive element-binding protein (CREB) on regulatory regions of the FoxP3 gene, a condition that is associated with an impaired acquisition of their suppressive capacity in vitro. To corroborate our findings in a human model of autoimmunity, we measured CREB phosphorylation and FoxP3 levels in iTreg cells from treatment-naïve relapsing-remitting (RR)-multiple sclerosis (MS) subjects. Interestingly, both phospho-CREB and FoxP3 induction directly correlated and were significantly reduced in RR-MS patients, suggesting a previously unknown mechanism involved in the induction and function of human iTreg cells.

The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.

This review critically examines the evolving landscape of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors, with a particular focus on the metabolic challenges within the tumor microenvironment. CAR T-cell therapy has demonstrated remarkable success in hematologic malignancies, yet its efficacy in solid tumors remains limited. A significant barrier is the hostile milieu of the tumor microenvironment, which impairs CAR T-cell survival and function. This review delves into the metabolic adaptations of cancer cells and their impact on immune cells, highlighting the competition for nutrients and the accumulation of immunosuppressive metabolites. It also explores emerging strategies to enhance CAR T-cell metabolic fitness and persistence, including genetic engineering and metabolic reprogramming. An integrated approach, combining metabolic interventions with CAR T-cell therapy, has the potential to overcome these constraints and improve therapeutic outcomes in solid tumors.

Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as "living drugs," their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post-translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic-based strategies to enhance T cell immunotherapy.

The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.

Regulatory T (Treg) cells are indispensable in maintaining the immune homeostasis and preventing autoimmune diseases. Regulatory T (Treg) cells include thymus derived Treg cells (tTregs) and peripherally induced Treg cells (iTreg), which are differentiated from antigen stimulated CD4+ naïve T cells in presence of TGFβ. tTregs are quite stable, and more immune suppressive, while iTreg cells are less stable, and are prone to differentiate into inflammatory T cells. Therefore, identification of small molecules that could promote the differentiation of iTreg cells is an attractive strategy for autoimmune diseases. Inhibition of AKT/mTOR pathway promotes their differentiation. Whether inhibition of Lck/Fyn kinase activity (upstream of AKT/mTOR pathway) can be used to promote the differentiation of iTreg cells has not been determined. Here, we showed that Srci1, a small molecular inhibitor of Lck/Fyn, promoted the differentiation of FOXP3+ iTreg cells. Srci1 treatment resulted in inhibition of phosphorylation of key components of AKT/mTOR pathway, including mTOR, p70 S6K, 4EBP1, and promoted the expression of Foxp3 and its target genes, thereby promoted differentiation of in vitro iTreg cells. Srci1 treated iTreg cells showed more similar gene expression profile to that of tTreg cells. Our results thus suggest that inhibition of Lck/Fyn kinase activity can promote the differentiation of iTreg cells, and may have implication in autoimmune diseases.

Tregs trafficking is controlled by CXCR4. In Renal Cell Carcinoma (RCC), the effect of the new CXCR4 antagonist, R54, was explored in peripheral blood (PB)-Tregs isolated from primary RCC patients.

PB-Tregs were isolated from 77 RCC patients and 38 healthy donors (HDs). CFSE-T effector-Tregs suppression assay, IL-35, IFN-γ, IL-10, TGF-β1 secretion, and Nrp-1+Tregs frequency were evaluated. Tregs were characterised for CTLA-4, PD-1, CD40L, PTEN, CD25, TGF-β1, FOXP3, DNMT1 transcriptional profile. PTEN-pAKT signalling was evaluated in the presence of R54 and/or triciribine (TCB), an AKT inhibitor. Methylation of TSDR (Treg-Specific-Demethylated-Region) was conducted.

R54 impaired PB-RCC-Tregs function, reduced Nrp-1+Tregs frequency, the release of IL-35, IL-10, and TGF-β1, while increased IFN-γ Teff-secretion. The CXCR4 ligand, CXCL12, recruited CD25+PTEN+Tregs in RCC while R54 significantly reduced it. IL-2/PMA activates Tregs reducing pAKT+Tregs while R54 increases it. The AKT inhibitor, TCB, prevented the increase in pAKT+Tregs R54-mediated. Moreover, R54 significantly reduced FOXP3-TSDR demethylation with DNMT1 and FOXP3 downregulation.

R54 impairs Tregs function in primary RCC patients targeting PTEN/PI3K/AKT pathway, reducing TSDR demethylation and FOXP3 and DNMT1 expression. Thus, CXCR4 targeting is a strategy to inhibit Tregs activity in the RCC tumour microenvironment.

The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

Inert naive CD4+ T (TN) cells differentiate into functional T helper (Th) or regulatory T (Treg) cell subsets upon encountering antigens, mediating properly directed immune responses. Although all TN cells can differentiate into any of the Th and Treg cell subsets, heterogeneity exists among TN cells. By constructing reporter mice to detect ongoing T cell receptor (TCR) signaling, we identify that interleukin (IL)-1β signaling affects TN cell characteristics, independent of tonic TCR signaling, which also alters TN cell phenotypes. IL-1β reversibly attenuates the differentiation potential of TN cells toward Treg cells. IL-1β signaling is elevated in the splenic TN cells, consequently attenuating their differentiation potential toward Treg cells. Aberrant elevation of IL-1β signaling augments colitogenic activities of TN cells. TN cells in patients with colitis exhibited elevated IL-1β signaling. We demonstrate that phenotypic alteration in TN cells by IL-1β is an important mechanism in the regulation of immune responses.

hnRNP A1 is an important RNA-binding protein that influences many stages of RNA processing, including transcription, alternative splicing, mRNA nuclear export, and RNA stability. However, the role of hnRNP A1 in immune cells, specifically CD4+ T cells, remains unclear. We previously showed that Akt phosphorylation of hnRNP A1 was dependent on TCR signal strength and was associated with Treg differentiation. To explore the impact of hnRNP A1 phosphorylation by Akt on CD4+ T cell differentiation, our laboratory generated a mutant mouse model, hnRNP A1-S199A (A1-MUT) in which the major Akt phosphorylation site on hnRNP A1 was mutated to alanine using CRISPR Cas9 technology. Immune profiling of A1-MUT mice revealed changes in the numbers of Tregs in the mesenteric lymph node. We found no significant differences in naive CD4+ T cell differentiation into Th1, Th2, Th17, or T regulatory cells (Tregs) in vitro. In vivo, Treg differentiation assays using OTII-A1-Mut CD4+ T cells exposed to OVA food revealed migration and homing defects in the A1-MUT but no change in Treg induction. A1-MUT mice were immunized with NP- keyhole limpet hemocyanin, and normal germinal center development, normal numbers of NP-specific B cells, and no change in Tfh numbers were observed. In conclusion, Akt phosphorylation of hnRNP A1 S199 does not play a role in CD4+ T cell fate or function in the models tested. This hnRNP A1-S199A mouse model should be a valuable tool to study the role of Akt phosphorylation of hnRNP A1-S199 in different cell types or other mouse models of human disease.

Staphylococcal superantigens induce massive activation of T cells and inflammation, leading to toxic shock syndrome. Paradoxically, increasing evidence indicates that superantigens can also induce immunosuppression by promoting regulatory T cell (Treg) development. In this study, we demonstrate that stimulation strength plays a critical role in superantigen-mediated induction of immunosuppressive human CD4+CD25+FOXP3+ T cells. Suboptimal stimulation by a low dose (1 ng/ml) of staphylococcal enterotoxin C1 (SEC1) led to de novo generation of Treg-like CD4+CD25+FOXP3+ T cells with strong suppressive activity. In contrast, CD4+CD25+ T cells induced by optimal stimulation with high-dose SEC1 (1 µg/ml) were not immunosuppressive, despite high FOXP3 expression. Signal transduction pathway analysis revealed differential activation of the PI3K signaling pathway and expression of PTEN in optimal and suboptimal stimulation with SEC1. Additionally, we identified that FOXP3 isoforms in Treg-like cells from the suboptimal condition were located in the nucleus, whereas FOXP3 in nonsuppressive cells from the optimal condition localized in cytoplasm. Sequencing analysis of FOXP3 isoform transcripts identified five isoforms, including a FOXP3 isoform lacking partial exon 3. Overexpression of FOXP3 isoforms confirmed that both an exon 2-lacking isoform and a partial exon 3-lacking isoform confer suppressive activity. Furthermore, blockade of PI3K in optimal stimulation conditions led to induction of suppressive Treg-like cells with nuclear translocation of FOXP3, suggesting that PI3K signaling impairs induction of Tregs in a SEC1 dose-dependent manner. Taken together, these data demonstrate that the strength of activation signals determined by superantigen dose regulates subcellular localization of FOXP3 isoforms, which confers suppressive functionality.

Ribonucleotide reductase M2 (RRM2) is a small subunit in ribonucleotide reductases, which participate in nucleotide metabolism and catalyze the conversion of nucleotides to deoxynucleotides, maintaining the dNTP pools for DNA biosynthesis, repair, and replication. RRM2 performs a critical role in the malignant biological behaviors of cancers. The structure, regulation, and function of RRM2 and its inhibitors were discussed. RRM2 gene can produce two transcripts encoding the same ORF. RRM2 expression is regulated at multiple levels during the processes from transcription to translation. Moreover, this gene is associated with resistance, regulated cell death, and tumor immunity. In order to develop and design inhibitors of RRM2, appropriate strategies can be adopted based on different mechanisms. Thus, a greater appreciation of the characteristics of RRM2 is a benefit for understanding tumorigenesis, resistance in cancer, and tumor microenvironment. Moreover, RRM2-targeted therapy will be more attention in future therapeutic approaches for enhancement of treatment effects and amelioration of the dismal prognosis.

Due to the increase of the elderly's population and related social and economic problems, it is very important to provide strategies on health. In this regard, induction of T lymphocytes responses, the most important cells of the immune system, may be a good approach. Among different agents considered as antiaging factors, mTORC1 pathway inhibitors are significant. So, the purpose of this study was to evaluate the effect of two mTORC1 inhibitors, Everolimus and Metformin, on age-related features of activated T cells.

Optimum doses of drugs was determined with evaluating the effect of treatments on IL-2 gene expression. T cells isolated from old and young mice were treated with drugs and PHA. IL-2 production was evaluated by ELISA. Also, the expression of CD28, PD-1, and KLRG-1, proliferation, and intracellular oxidative stress were assessed by flow cytometry-based assays, phenotyping, CFSE, and DCF-DA assay respectively.

Both drugs increased IL-2 production in the T cells of old mice. Also, using drugs especially Metformin could improve age-related phenotypical markers and increase the proliferation of T cells of old mice significantly. In addition, Metformin and Everolimus reduced intracellular oxidative stress in aged cells. However, the effect of both drugs on the T cells of young mice wasn't significant or was in opposite to the results of old mice T cells.

In line with studies noting mTOR inhibitors as antiaging drugs, Metformin and Everolimus may improve T cells affected from aging in vitro, and a decrease in intracellular oxidative stress may be one of their mechanism of function.

Regulatory T cells (Tregs) have critical roles in maintaining immune hemostasis and have important anti-inflammatory functions in diseases. Recently, we identified that CX-5461 (a selective RNA polymerase I inhibitor and p53 activator) acted as a potent immunosuppressive agent, which prevented allogeneic acute rejection in animal models via a molecular mechanism distinct from all those of conventional immunosuppressive drugs. Unexpectedly, we discovered that CX-5461 could promote Treg differentiation. In this review, we have summarized the evidence for a potential role of p53 in mediating Treg differentiation and its possible mechanisms, including regulation of FoxP3 transcription, regulation of the expression of PTEN (phosphatase and tensin homolog), as well as protein-protein interaction with the transcription factor STAT5 (signal transducer and activator of transcription 5). Evidence also suggests that pharmacological p53 activators may potentially be used to boost Treg-mediated immune tolerance. Based on these data, we argue that novel p53 activators such as CX-5461 may represent a distinct class of immunosuppressants that repress conventional T cell-mediated alloimmunity with concomitant boosting of Treg-dependent immune tolerance.

Regulatory T cells are fundamental for the induction and maintenance of immune homeostasis, with their dysfunction resulting in uncontrolled immune responses and tissue destruction predisposing to autoimmunity, transplant rejection and several inflammatory and metabolic disorders. Recent discoveries have demonstrated that metabolic processes and mitochondrial function are critical for the appropriate functioning of these cells in health, with their metabolic adaptation, influenced by microenvironmental factors, seen in several pathological processes. Upon activation regulatory T cells rearrange their oxidation-reduction (redox) system, which in turn supports their metabolic reprogramming, adding a layer of complexity to our understanding of cellular metabolism. Here we review the literature surrounding redox homeostasis and metabolism of regulatory T cells to highlight new mechanistic insights of these interlinked pathways in immune regulation.

Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIH treatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.

Forkhead Box P3 (FOXP3) is crucial for the development and suppressive function of human regulatory T cells (Tregs). There are two predominant FOXP3 splicing isoforms in healthy humans, the full-length isoform and the isoform lacking exon 2, with different functions and regulation mechanisms. FOXP3 splicing isoforms show distinct abilities in the cofactor interaction and the nuclear translocation, resulting in different effects on the differentiation, cytokine secretion, suppressive function, linage stability, and environmental adaptation of Tregs. The balance of FOXP3 splicing isoforms is related to autoimmune diseases, inflammatory diseases, and cancers. In response to environmental challenges, FOXP3 transcription and splicing can be finely regulated by T cell antigen receptor stimulation, glycolysis, fatty acid oxidation, and reactive oxygen species, with various signaling pathways involved. Strategies targeting energy metabolism and FOXP3 splicing isoforms in Tregs may provide potential new approaches for the treatment of autoimmune diseases, inflammatory diseases, and cancers. In this review, we summarize recent discoveries about the FOXP3 splicing isoforms and address the metabolic regulation and specific functions of FOXP3 splicing isoforms in Tregs.

Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome. RA interfered with extranuclear RARα signaling, causing suboptimal TCR activation while enhancing FOXP3+ regulatory T cell conversion. TCR activation induced the expression of CRABP2, which translocates RA to the nucleus. Deletion of Crabp2 led to increased RA in the cytoplasm and interfered with signalosome-RARα, resulting in impaired anti-pathogen immunity and suppressed autoimmune disease. Our findings underscore the significance of subcellular RA/RARα signaling in T cells and identify extranuclear RARα as a component of the TCR signalosome and a determinant of immune responses.

Regulatory T (Treg) cells that express the transcription factor forkhead box protein P3 (FOXP3) are naturally present in the immune system and have roles in the maintenance of immunological self-tolerance and immune system and tissue homeostasis. Treg cells suppress T cell activation, expansion and effector functions by various mechanisms, particularly by controlling the functions of antigen-presenting cells. They can also contribute to tissue repair by suppressing inflammation and facilitating tissue regeneration, for example, via the production of growth factors and the promotion of stem cell differentiation and proliferation. Monogenic anomalies of Treg cells and genetic variations of Treg cell functional molecules can cause or predispose patients to the development of autoimmune diseases and other inflammatory disorders, including kidney diseases. Treg cells can potentially be utilized or targeted to treat immunological diseases and establish transplantation tolerance, for example, by expanding natural Treg cells in vivo using IL-2 or small molecules or by expanding them in vitro for adoptive Treg cell therapy. Efforts are also being made to convert antigen-specific conventional T cells into Treg cells and to generate chimeric antigen receptor Treg cells from natural Treg cells for adoptive Treg cell therapies with the aim of achieving antigen-specific immune suppression and tolerance in the clinic.

Immune cell function among the myocardium, now more than ever, is appreciated to regulate cardiac function and pathophysiology. This is the case for both innate immunity, which includes neutrophils, monocytes, dendritic cells, and macrophages, as well as adaptive immunity, which includes T cells and B cells. This function is fueled by cell-intrinsic shifts in metabolism, such as glycolysis and oxidative phosphorylation, as well as metabolite availability, which originates from the surrounding extracellular milieu and varies during ischemia and metabolic syndrome. Immune cell crosstalk with cardiac parenchymal cells, such as cardiomyocytes and fibroblasts, is also regulated by complex cellular metabolic circuits. Although our understanding of immunometabolism has advanced rapidly over the past decade, in part through valuable insights made in cultured cells, there remains much to learn about contributions of in vivo immunometabolism and directly within the myocardium. Insight into such fundamental cell and molecular mechanisms holds potential to inform interventions that shift the balance of immunometabolism from maladaptive to cardioprotective and potentially even regenerative. Herein, we review our current working understanding of immunometabolism, specifically in the settings of sterile ischemic cardiac injury or cardiometabolic disease, both of which contribute to the onset of heart failure. We also discuss current gaps in knowledge in this context and therapeutic implications.

Type 1 diabetes (T1D) is a polygenic disease and does not follow a mendelian pattern. Inborn errors of immunity (IEIs), on the other hand, are caused by damaging germline variants, suggesting that T1D and IEIs have nothing in common. Some IEIs, resulting from mutations in genes regulating regulatory T-cell homeostasis, are associated with elevated incidence of T1D. The genetic spectrum of IEIs is gradually being unraveled; consequently, molecular pathways underlying human monogenic autoimmunity are being identified. There is an appreciable overlap between some of these pathways and the genetic variants that determine T1D susceptibility, suggesting that after all, IEI and T1D are 2 sides of the same coin. The study of monogenic IEIs with a variable incidence of T1D has the potential to provide crucial insights into the mechanisms leading to T1D. These insights contribute to the definition of T1D endotypes and explain disease heterogeneity. In this review, we discuss the interconnected pathogenic pathways of autoimmunity, β-cell function, and primary immunodeficiency. We also examine the role of environmental factors in disease penetrance as well as the circumstantial evidence of IEI drugs in preventing and curing T1D in individuals with IEIs, suggesting the repositioning of these drugs also for T1D therapy.

Protein phosphatase 2A (PP2A) is a serine-threonine phosphatase that plays an important role in the regulation of cell proliferation and signal transduction. The catalytic activity of PP2A is integral in the maintenance of physiological functions which gets severely impaired in its absence. PP2A plays an essential role in the activation, differentiation, and functions of T cells. PP2A suppresses Th1 cell differentiation while promoting Th2 cell differentiation. PP2A fosters Th17 cell differentiation which contributes to the pathogenesis of systemic lupus erythematosus (SLE) by enhancing the transactivation of the Il17 gene. Genetic deletion of PP2A in Tregs disrupts Foxp3 expression due to hyperactivation of mTORC1 signaling which impairs the development and immunosuppressive functions of Tregs. PP2A is important in the induction of Th9 cells and promotes their antitumor functions. PP2A activation has shown to reduce neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) and is now used to treat multiple sclerosis (MS) clinically. In this review, we will discuss the structure and functions of PP2A in T cell differentiation and diseases and therapeutic applications of PP2A-mediated immunotherapy.

CC chemokine receptor 6 (CCR6) is one of the members of the G-protein-coupled receptor (GPCR) family that is upregulated in many immune-related cells, such as B lymphocytes, effector and memory T cells, regulatory T cells, and immature dendritic cells. The coordination between CCR6 and its ligand CC motif chemokine ligand 20 (CCL20) is deeply involved in the pathogenesis of various diseases, such as cancer, psoriasis, and autoimmune diseases. Thus, CCR6 is an attractive target for therapy and is being investigated as a diagnostic marker for various diseases. In a previous study, we developed an anti-mouse CCR6 (mCCR6) monoclonal antibody (mAb), C₆Mab-13 (rat IgG₁, kappa), that was applicable for flow cytometry by immunizing a rat with the N-terminal peptide of mCCR6. In this study, we investigated the binding epitope of C₆Mab-13 using an enzyme-linked immunosorbent assay (ELISA) and the surface plasmon resonance (SPR) method, which were conducted with respect to the synthesized point-mutated-peptides within the 1-20 amino acid region of mCCR6. In the ELISA results, C₆Mab-13 lost its ability to react to the alanine-substituted peptide of mCCR6 at Asp11, thereby identifying Asp11 as the epitope of C₆Mab-13. In our SPR analysis, the dissociation constants (K_D) could not be calculated for the G9A and D11A mutants due to the lack of binding. The SPR analysis demonstrated that the C₆Mab-13 epitope comprises Gly9 and Asp11. Taken together, the key binding epitope of C₆Mab-13 was determined to be located around Asp11 on mCCR6. Based on the epitope information, C₆Mab-13 could be useful for further functional analysis of mCCR6 in future studies.

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

Immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the treatment of various malignancies. By unleashing the natural immunological brake of the immune system, ICIs were initially considered an effective, gentle therapy with few side effects. However, accumulated clinical knowledge reveals that ICIs are associated with inflammation and tissue damage in multiple organs, leading to immune-related adverse effects (irAEs). Most irAEs involve the skin and gastrointestinal tract; however, cardiovascular involvement is associated with very high mortality rates, and its underlying pathomechanisms are poorly understood. Ranging from acute myocarditis to chronic cardiomyopathies, ICI-induced cardiotoxicity can present in various forms and entities. Revealing the inciting factors, understanding the pathogenesis, and identifying effective treatment strategies are needed to improve the care of tumor patients and our understanding of the immune and cardiovascular systems.

To achieve a healthy and functional immune system, a delicate balance exists between the activation of conventional T cells (Tcon cells) and the suppression by regulatory T cells (Treg). The tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, shapes this 'activation-suppression' balance by modulating Tcon cell resistance to Treg-mediated suppression. Treg cells also express SHP-1, but its role in influencing Treg function is still not fully understood.

We generated a Treg-specific SHP-1 deletion model, Foxp3Cre+ Shp-1f/f , to address how SHP-1 affects Treg function and thereby contributes to T cell homeostasis using a combination of ex vivo studies and in vivo models of inflammation and autoimmunity.

We show that SHP-1 modulates Treg suppressive function at different levels. First, at the intracellular signaling level in Treg cells, SHP-1 attenuates TCR-dependent Akt phosphorylation, with loss of SHP-1 driving Treg cells towards a glycolysis pathway. At the functional level, SHP-1 expression limits the in vivo accumulation of CD44hiCD62Llo T cells within the steady state Tcon populations (both CD8+ as well as CD4+ Tcon). Further, SHP-1-deficient Treg cells are less efficient in suppressing inflammation in vivo; mechanistically, this appears to be due to a failure to survive or a defect in migration of SHP-1-deficient Treg cells to peripheral inflammation sites.

Our data identify SHP-1 as an important intracellular mediator for fine-tuning the balance between Treg-mediated suppression and Tcon activation/resistance.

CD4⁺ T cells are critical components of the adaptive immune system. The T cell receptor (TCR) and co-receptor signaling cascades shape the phenotype and functions of CD4⁺ T cells. TCR signaling plays a crucial role in T cell development, antigen recognition, activation, and differentiation upon recognition of foreign- or auto-antigens. In specific autoimmune conditions, altered TCR repertoire is reported and can predispose autoimmunity with organ-specific inflammation and tissue damage. TCR signaling modulates various signaling cascades and regulates epigenetic and transcriptional regulation during homeostasis and disease conditions. Understanding the mechanism by which coreceptors and cytokine signals control the magnitude of TCR signal amplification will aid in developing therapeutic strategies to treat inflammation and autoimmune diseases. This review focuses on the role of the TCR signaling cascade and its components in the activation, differentiation, and plasticity of various CD4⁺ T cell subsets.

Foxp3+ T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.

As a common primary intracranial tumor, the diagnosis and therapy of low-grade glioma (LGG) remains a pivotal barrier. Cuproptosis, a new way induces cell death, has attracted worldwide attention. However, the relationship between cuproptosis and LGG remains unknown. Our study is all about finding out if there are any genes related to coproptosis that can be used to predict the outcome of LGG.

RNA data and clinical information were selected from Cancer Genome Atlas (TCGA) datasets and the Genotype-Tissue Expression (GTEx), 5 lncRNAs (GAS5.AS1, MYLK.AS1, AC142472.1, AC011346.1, AL359643.3) were identified by Cox univariate and multivariate regression, as well as LASSO Cox regression. In the training and test sets, a dual validation of the predictive signature comprised of these 5 lncRNAs was undertaken. The findings demonstrate that the risk model is able to predict the survival regression of LGG patients and has a good performance in either the KM curve approach or the ROC curve. GO, GSEA and KEGG were carried out to explore the possible molecular processes that affecting the prognosis of LGG. The characteristics of immune microenvironment were investigated by using CIBERSORT, ESTIMATE and ssGSEA.

We identified five lncRNAs related with cuproptosis that were closely associated with the prognosis of LGG and used these five lncRNAs to develop a risk model. Using this risk model, LGG patients were then divided into high-risk and low-risk groups. The two patient groups had significantly distinct survival characteristics. Analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the differential genes of the two patient groups were primarily concentrated in neural active ligand-receptor interaction and cytokine-cytokine receptor interaction. The ssGSEA score determined the information related to immune infiltration, and the two groups were differentially expressed in immune subpopulations such as T cells and B cells as well.

Our study discovered 5 cuproptosis-related lncRNAs which contribute to predicting patients' survival of LGG and provide ideas for the exploration of new targets for LGG in the future.