Kidney transplantation (KTx) is the method of choice for treating kidney failure. Identifying biomarkers predictive of transplant (Tx) outcomes is critical to optimize KTx; however, the immunosuppressive therapies required after KTx must also be considered. We applied targeted bisulfite sequencing (TBS-seq) to PBMCs isolated from 90 patients, with samples collected pre- and post-Tx (day 90), to measure DNA methylation changes. Our findings indicate that the PBMC DNA methylome is significantly affected by induction immunosuppression with anti-thymocyte globulin (ATG). We discovered that the risk of infection can be predicted using DNA methylation profiles, but not gene expression profiles. Specifically, 515 CpG loci associated with 275 genes were significantly impacted by ATG induction, even after accounting for age, sex, and cell-type composition. Notably, ATG-associated hyper-methylation down-regulates genes critical for immune response. In conclusion, this clinical omics study reveals that the immunosuppressant ATG profoundly impacts the DNA methylome of KTx recipients and identifies biomarkers that could be used in pre-Tx screening of patients vulnerable to infection, thereby informing immunosuppression strategies post-Tx.

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.

Soluble immune checkpoints play an important role in peripheral tolerance that has seldom been investigated in Graves' disease (GD) and thyroid eye disease (TED).

The objective of this work is to examine the alteration of soluble immune checkpoints in GD and TED.

We performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum from 50 GD patients without TED, 28 GD patients with TED, and 40 healthy controls. The association with demographic, serologic, clinical features and 27 cytokines was analyzed. A follow-up was conducted in GD patients without TED. Functional outcomes of sLAG-3 and sGITR were assessed in cell cultures using rh-LAG3, rh-GITR, an antagonistic LAG-3 antibody, and an antagonistic GITR antibody.

GD Patients with TED had distinct sICP and cytokine profiles compared with GD patients without TED. Active patients with TED exhibited elevation in the levels of sBTLA, sLAG-3, sGITR, sCD80, sCD86, and sPD-L1. Further, GD patients without TED with high sBTLA, sCD27, and sCD40 levels at baseline showed a better improvement in thyrotropin receptor antibody titers after antithyroid drug treatment. Adding recombinant human GITR and LAG-3 to peripheral blood mononuclear cell cultures resulted in increased inflammatory cytokine secretion and decreased anti-inflammatory cytokine secretion.

The present study uncovers disturbed soluble immune checkpoints and cytokines in GD patients with and without TED and may pave the way for novel immunological screening, allowing for identification of patients with TED at higher risk of developing active disease and patients with GD a better treatment response after antithyroid drug treatment.

This study aims to analyze CD27 expression in various subsets of CD4+ T cells in peripheral blood, explore the functional characteristics of the CD27+ subsets in regulatory T cells (Tregs) and CD4+ T cells, and assess their immunological alterations in newly diagnosed systemic lupus erythematosus (SLE) patients.

Peripheral blood was collected from 34 newly diagnosed, untreated SLE patients and 22 healthy controls. Flow cytometry was used to analyze CD27 expression on T cell subsets, comparing the functional markers between CD27+ and CD27- subsets. CD27 expression on Tregs and total CD4+ T cells in SLE patients and healthy controls were compared. ROC curves were constructed, and areas under the curve (AUCs) was calculated to evaluate the diagnostic value of CD27-related T cell subsets for SLE.

The proportion of Tregs in the peripheral blood of SLE patients was increased, and CD27 expression was higher in Tregs than in CD4+ T cells in healthy individuals. CD27+ CD4+ T cells exhibited higher CD45RA and lower CD226 expression. CD27+ Tregs showed higher Helios and TIGIT expression and lower CD226 expression. CD27+ cell proportions in both CD4+ T cells and Tregs were significantly reduced in SLE patients. The AUC for CD27-related T cell subsets in diagnosing newly diagnosed SLE ranged from 0.6238 to 0.86.

CD27+ CD4+ T cells show reduced activation features, while CD27+ Tregs exhibit enhanced regulatory potential. Their decreased proportions in SLE patients suggest early immune dysregulation.

Polymyositis (PM) is a systemic autoimmune disease characterized by muscular inflammatory infiltrates and degeneration. T-cell immunoreceptor with Ig and ITIM domains (TIGIT) contributes to immune tolerance by inhibiting T cell-mediated autoimmunity. Here, we show that a reduced expression of TIGIT in CD4+ T cells from patients with PM promotes these cells' differentiation into Th1 and Th17 cells, which could be rescued by TIGIT overexpression. Knockout of TIGIT enhances muscle inflammation in a mouse model of experimental autoimmune myositis. Mechanistically, we find that TIGIT deficiency enhances CD28-mediated PI3K/AKT/mTOR co-stimulatory pathway, which promotes glucose oxidation, citrate production, and increased cytosolic acetyl-CoA levels, ultimately inducing epigenetic reprogramming via histone acetylation. Importantly, pharmacological inhibition of histone acetylation suppresses the differentiation of Th1 and Th17 cells, alleviating muscle inflammation. Thus, our findings reveal a mechanism by which TIGIT directly affects the differentiation of Th1 and Th17 T cells through metabolic‒epigenetic reprogramming, with important implications for treating systemic autoimmune diseases.

In this study, we found that the CD8+CD45RA+CCR7- T cell subpopulation was increased in the peripheral blood of patients with primary Sjögren's syndrome (pSS) compared with healthy donors. Moreover, both CD8+TIM-3+ T cells and CD8+CD45RA+CCR7- T cells were positively correlated with serum anti-SSA antibody concentrations in patients. In animal experiments, prolonged administration of β-glucan (whole glucan particle [WGP]) effectively reduced the onset and progression of pSS. Compared with the control group, the WGP-treated group showed a significant reduction in the proportions of CD4+PD-1+ T cells, CD4+TIM-3+ T cells, CD8+PD-1+ T cells, CD8+TIM-3+ T cells, and CD8+CD45RA+CCR7- T cells in the spleens and peripheral blood of non-obese diabetic mice. Notably, β-glucan exhibited therapeutic efficacy comparable to that of hydroxychloroquine sulfate, a conventional treatment for pSS. These findings suggest that the CD8+CD45RA+CCR7- T cell subpopulation may represent a promising new therapeutic target for the disease.

Bladder cancer (BLCA) is the tenth most commonly diagnosed cancer and poses a significant challenge due to its complexity and associated high morbidity and mortality rates in the absence of optimal treatment. The tumor microenvironment (TME) is recognized as a critical factor in tumor initiation, progression and therapeutic response, and offers numerous potential targets for intervention. A comprehensive understanding of immune infiltration patterns in BLCA is essential for the development of effective prevention and treatment strategies. In this study, bioinformatics analysis was used to identify differentially expressed genes (DEGs) and tumor-infiltrating immune cells (TIICs) between BLCA tissues and adjacent normal tissues. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis were used to identify the top 10 hub genes with the most significant co-expression effects, and their potential relationship with patient prognosis was then predicted. The random survival forest (RSF) model was used to further identify six variables among the hub genes and establish a novel scoring system, defined as the tumor-infiltrating immune score (TIIS) to predict the prognosis of BLCA patients. In addition, the correlation analysis between TIIS and drug sensitivity was investigated using the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) databases. Patients with high TIIS were found to have a poor prognosis but may be more sensitive to Cisplatin and certain novel agents. This study provided a systematic analysis of immune cell infiltration in BLCA and established TIIS to predict patient prognosis and the efficacy of specific drugs in the treatment of BLCA.

The increasing success of organ transplantation has significantly improved survival for patients with end-stage diseases, yet it introduces a complex dilemma: the elevated risk for the development of de novo gastrointestinal (GI) tumors. The sustained immunosuppression required to maintain graft function paradoxically undermines the body's natural defenses against cancer, leading to a higher incidence, aggressive progression, and atypical presentations of GI tumors among transplant recipients compared with the general population. This presents a pressing challenge: balancing the dual imperatives of preventing graft rejection and effectively managing malignancies. Current treatment paradigms, including surgical approaches, chemotherapy, radiation therapy, and the emerging role of immunotherapy, are fraught with complexities due to the altered immune landscape in these patients. This review underscores the critical need to understand the multifaceted relationship between post-transplantation immunosuppression and tumorigenesis, providing a comprehensive exploration of epidemiologic shifts, pathophysiologic insights, and the intricacies of the tumor microenvironment in this unique patient population. Understanding and managing GI tumors in transplant recipients is not only a clinical challenge, but also a necessary frontier in transplant oncology, promising to refine therapeutic strategies and improve the longevity and quality of life for this growing patient cohort.

Autoimmune diseases result from chronic and dysregulated activation of the immune system, culminating in pathological self-tissue damage. These disorders are primarily driven by adaptive immune responses, particularly those mediated by T and B lymphocytes, which mistakenly target self-antigens expressed in host tissues. In rheumatoid arthritis (RA), the pathogenesis is closely associated with the emergence of tissue-invasive effector T cells and the functional impairment of regulatory T cells (Tregs), both of which play pivotal roles in disease progression. Therapeutic interventions targeting these dysregulated T cell populations have emerged as a promising strategy for RA management. Although synthetic immunosuppressants remain the mainstay of RA treatment, their long-term application is often hampered by adverse effects, diminished therapeutic efficacy, and poor patient adherence. These limitations highlight the critical need for the development of novel therapeutic approaches. Natural compounds derived from medicinal plants have been widely utilized in the clinical management of RA, with growing evidence supporting their immunomodulatory potential, particularly in restoring T cell-mediated immune tolerance. This review aims to provide a comprehensive overview of recent advances in understanding T cell dysregulation in RA and to elucidate the mechanisms through which natural compounds regulate immune responses. By integrating current findings, this work seeks to offer a theoretical foundation for the optimized use of natural compounds in the treatment of RA, while exploring their potential in advancing precision medicine and personalized therapeutic strategies.

Antigen-specific immunotherapy shows potential for inducing long-term immune tolerance in type 1 diabetes (T1D), yet its clinical application is hampered by uncertainty regarding dominant epitopes. Conversely, non-antigen-specific treatments such as anti-CD3 monoclonal antibodies (mAbs) present a more straightforward approach but struggle to maintain tolerance after treatment. Addressing these issues is critical for advancing T1D therapies.

The phenotypic and metabolic properties of two subsets of exhausted CD8+ T cells were analyzed in both humans and NOD mice. T-cell receptor (TCR) diversity and Bulk RNA sequencing provided insights into the transcriptomic profiles and TCR reactivity of these cells. Mechanistic studies were conducted using the HEK-293 T cell line and primary cells. Single-cell RNA sequencing (scRNA-seq) was applied to evaluate the characteristics of different CD8+ T cell subsets following two types of immunotherapies. In NY8.3 mice, the effect of mitochondrial fission inhibitors on immunotherapy results was evaluated. Final validation was carried out with peripheral blood mononuclear cells (PBMCs) from T1D patients.

Our study reveals the diversity of two distinct exhausted CD8+ T cell subsets in T1D through flow cytometry, highlighting unique clinical features, phenotypes, and functions. Notable differences in TCR reactivity and metabolic pathways between these subsets were identified through TCR sequencing and transcriptomic analyses in NOD mice. Both antigen-specific and non-antigen-specific stimuli produced unique exhausted CD8+ T cell subsets. Our research identified leucine-rich repeat kinase 2 (Lrrk2) as a key regulator of mitochondrial fission, influencing the interconversion of exhausted CD8+ T cell subsets by phosphorylating dynamin-related protein 1 (DRP1) at serine 637 (Ser637) and serine 616 (Ser616). scRNA-seq confirmed that antigen-specific immunotherapy effectively suppresses T cell signaling, induces exhaustion, and promotes the development of terminally exhausted T (TEX) cells. Mitochondrial division inhibitor 1 (Mdivi-1) enhanced the therapeutic effect of anti-CD3 mAb treatment by promoting the development of more TEX cells.

Our results point to a new immunotherapeutic approach that targets exhausted CD8+ T cells' energy metabolism, offering valuable insights for advancing clinical strategies in T1D therapy.

Rationale: Programmed cell death protein 1 (PD-1)-expressing CD8+ T cells are typically associated with exhaustion in cancer and infections, but their role in autoimmune diseases, particularly lupus nephritis (LN), remains less understood. Understanding the characteristics and functions of PD-1+CD8+ T cells in LN could help identify novel therapeutic strategies. Methods: We analyzed the abundance and phenotypes of PD-1+CD8+ T cells in LN patients and NZB/W F1 mice. Single-cell RNA sequencing (scRNA-seq) was used to delineate subsets and TCR clonal diversity in PD-1+CD8+ T cells in NZB/W F1 mice. The therapeutic efficacy of a PD-L1 Fc fusion protein on kidney pathology and proteinuria in NZB/W F1 mice was evaluated. In addition, the inhibitory mechanism of PD-1 in CD8+ T cells were further explored using RNA-seq, q-PCR, flow cytometry, and Western blot. Results: PD-1+CD8+ T cells were enriched in LN patients and NZB/W F1 mice, exhibiting elevated activation markers and cytotoxic molecules compared to PD-1- cells. scRNA-seq identified seven distinct subsets with diverse effector functions and robust TCR clonal expansion in the kidney of NZB/W F1 mice with severe disease. PD-L1 Fc treatment reduced kidney damage and proteinuria in NZB/W F1 mice, which correlated with decreased frequencies of PD-1+CD8+ and IFN-γ+CD8+ T cells. Mechanistically, PD-L1 Fc inhibited Stat1 phosphorylation, T-bet expression, and IFN-γ production in CD8+ T cells. Conclusion: These findings show that PD-1+CD8+ T cells in LN are hyperactive, clonally expanded, and contribute to disease progression. Targeting the PD-1/PD-L1 pathway with PD-L1 Fc effectively reduced kidney pathology in a murine model of LN, underscoring the potential of modulating PD-1 signaling as a treatment strategy for LN.

Tolerogenic antigen-presenting cells (APCs) are promising as therapeutics for suppressing T cell activation in autoimmune diseases. However, the isolation and ex vivo manipulation of autologous APCs is costly, and the process is customized for each patient. Here we show that tolerogenic APCs can be generated in vivo by delivering, via lipid nanoparticles, messenger RNA coding for the inhibitory protein programmed death ligand 1. We optimized a lipid-nanoparticle formulation to minimize its immunogenicity by reducing the molar ratio of nitrogen atoms on the ionizable lipid and the phosphate groups on the encapsulated mRNA. In mouse models of rheumatoid arthritis and ulcerative colitis, subcutaneous delivery of nanoparticles encapsulating mRNA encoding programmed death ligand 1 reduced the fraction of activated T cells, promoted the induction of regulatory T cells and effectively prevented disease progression. The method may allow for the engineering of APCs that target specific autoantigens or that integrate additional inhibitory molecules.

Systemic lupus erythematosus (SLE) is an autoimmune disease with unclear etiology. T cell exhaustion (TEX) suppresses the immune response and can be a potential therapeutic strategy for autoimmune diseases. Therefore, this study primarily investigated the mechanism by which TEX influences SLE, offering a novel target for its treatment.

GSE72326 and GSE81622 were utilized in this study. TEX related genes (TEX-RGs) were obtained from the published literature. Differentially expressed genes (DEGs) were obtained through differential expression analysis. Subsequently, candidate genes were selected by overlapping DEGs and TEX-RGs. These candidate genes underwent protein-protein interactions (PPIs) analysis for further screening. Machine learning was applied to identify candidate key genes from the PPI-identified genes. The candidate key genes exhibiting an area under the receiver operating characteristic (ROC) curve (AUC) greater than 0.7, along with consistent expression trends and significant differences in GSE72326 and GSE81622 were defined as biomarkers. Additionally, enrichment analysis, immune infiltration analysis, chemical compounds prediction and molecular docking were carried out. Importantly, the biomarkers were validated for expression by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

The biomarkers MX1, LY6E, IFI44 and OASL were screened by overlapping 327 DEGs and 1,408 TEX-RGs. Gene set enrichment analysis (GSEA) showed that there was a significant positive correlation between the expression of these biomarkers and immune-related pathways, such as the NOD-like receptor signaling pathway, Toll-like receptor signaling pathway and RIG-I-like receptor signaling pathway significant positive correlation. The immune infiltration of 8 types of immune cells differed significantly in SLE. Naive B cells, resting memory CD4 T cells and resting NK cells were significantly down-regulated in the SLE group. 4 biomarkers showed the highest correlation with resting memory CD4 T cells. Bisphenol A targeted OASL and LY6E, whereas acetaminophen targeted IFI44 and MX1.The binding activity between the biomarkers and the chemical compounds targeting them was very strong. Finally, RT-qPCR expression of MX1, LY6E, IFI44 and OASL was consistent with the results of the dataset.

MX1, LY6E, IFI44 and OASL were identified as biomarkers related to TEX in SLE. These biomarkers could be detected in the blood for early diagnosis of the disease or to monitor the efficacy of the disease treatment, thus providing a new target for the management of SLE.

This review explores the emerging role of T cell exhaustion in allergic diseases and allergen immunotherapy (AIT). It aims to synthesize current knowledge on the mechanisms of T cell exhaustion, evaluate its potential involvement in allergic inflammation, and assess its implications as a novel biomarker for predicting and monitoring AIT efficacy.

Recent studies highlight that T cell exhaustion, characterized by co-expression of inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3), diminished cytokine production, and altered transcriptional profiles, may suppress type 2 inflammation in allergic diseases. In allergic asthma, exhausted CD4 + T cells exhibit upregulated inhibitory receptors, correlating with reduced IgE levels and airway hyperreactivity. During AIT, prolonged high-dose allergen exposure drives allergen-specific Th2 and T follicular helper (Tfh) cell exhaustion, potentially contributing to immune tolerance. Notably, clinical improvements in AIT correlate with depletion of allergen-specific Th2 cells and persistent expression of exhaustion markers (e.g., PD-1, CTLA-4) during maintenance phases. Blockade of inhibitory receptors (e.g., PD-1) enhances T cell activation, underscoring their dual regulatory role in allergy. T cell exhaustion represents a double-edged sword in allergy: it may dampen pathological inflammation in allergic diseases while serving as a mechanism for AIT-induced tolerance. The co-expression of inhibitory receptors on allergen-specific T cells emerges as a promising biomarker for AIT efficacy. Future research should clarify the transcriptional and metabolic drivers of exhaustion in allergy, validate its role across diverse allergic conditions, and optimize strategies to harness T cell exhaustion for durable immune tolerance. These insights could revolutionize therapeutic approaches and biomarker development in allergy management.

JIA is the most common rheumatic disease of childhood; the pathogenesis is associated with T-cell activation. T-cell activation can be counterbalanced by signals generated by inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG-3 and TIM-3. Here, we identify the role of IRs in the pathogenesis of different JIA subtypes.

In total, we included 67 oligoarticular JIA, 12 IgM-RF negative polyarticular JIA, 17 enthesitis-related arthritis, 11 systemic JIA patients and 10 healthy controls. We collected plasma (and SF) samples from the patients either at the onset or during a flare of their disease. We measured the soluble levels of co-IRs (IL-2Rα, 4-1BB, CD86, TGF-β1, CTLA-4, PD-L1, PD-1, TIM-3, LAG- 3, Galectin-9) by cytometric bead array kits and their cellular expression (PD-1, CTLA-4, TIM-3, LAG-3) by flow cytometry. We compared the plasma levels and cellular expressions of different co-IRs within different JIA subgroups.

The polyarticular JIA group was different from the three other examined JIA subgroups, having higher levels of plasma sCTLA-4 (P < 0.001), sPD-1 (P < 0.05) and s4-1BB (P < 0.05) when compared with the other JIA subgroups and healthy controls. We analysed the cellular surface expression of different co-IRs on the peripheral blood mononuclear cells of different JIA subtypes. Similar to plasma levels, both the percentage (P < 0.05) and the mean fluorescence intensity (P < 0.01) of CTLA4 expression were higher in the polyarticular JIA subgroup.

This is the first report studying the expression profile of different co-IRs in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA.

Gene expression studies often use bulk RNA sequencing of mixed cell populations because single cell or sorted cell sequencing may be prohibitively expensive. However, mixed cell studies may miss expression patterns that are restricted to specific cell populations. Computational deconvolution can be used to estimate cell fractions from bulk expression data and infer average cell-type expression in a set of samples (e.g., cases or controls), but imputing sample-level cell-type expression is required for more detailed analyses, such as relating expression to quantitative traits, and is less commonly addressed. Here, we assessed the accuracy of imputing sample-level cell-type expression using a real dataset where mixed peripheral blood mononuclear cells (PBMC) and sorted (CD4, CD8, CD14, CD19) RNA sequencing data were generated from the same subjects (N=158), and pseudobulk datasets synthesised from eQTLgen single cell RNA-seq data. We compared three domain-specific methods, CIBERSORTx, bMIND and debCAM/swCAM, and two cross-domain machine learning methods, multiple response LASSO and ridge, that had not been used for this task before. We also assessed the methods according to their ability to recover differential gene expression (DGE) results. LASSO/ridge showed higher sensitivity but lower specificity for recovering DGE signals seen in observed data compared to deconvolution methods, although LASSO/ridge had higher area under curves than deconvolution methods. Machine learning methods have the potential to outperform domain-specific methods when suitable training data are available.

In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of BATF and not PD1 decreased inhibitory molecules expression and restored the survival and function of UFL1-deficient TVM cells. Our findings demonstrate a key role of UFL1 in inhibiting the exhaustion of TVM cells and promoting their survival and function.

Immunosuppressive agents, although indispensable in the treatment of chronic kidney diseases (CKD), could compromise the patient's immune function. The risk factor for in-hospital mortality in immunocompromised CKD patients with severe infections remain elusive.

We conducted a retrospective analysis of the clinical data of CKD patients who received immunosuppressive agents and presented severe infections. The cohort comprised 272 patients, among whom 73 experienced mortalities during their hospitalization. Logistic regression was employed on the training set to identify key feature variables and construct a predictive model for in-hospital mortality among immunocompromised CKD patients following severe infections. To facilitate clinical application, we constructed a nomogram to visually represent the predictive model.

Our findings indicate that ventilator use, vasoactive drug administration, elevated lactate dehydrogenase (LDH), total bilirubin (TBIL) levels, and persistent lymphopenia(PL) are effective predictors of in-hospital mortality in immunocompromised patients with severe infections. These variables were subsequently incorporated to construct a robust prognostic model. Our model demonstrated excellent discriminative ability (AUC = 0.959, 95% CI, 0.924-0.994), significantly outperforming the Sequential Organ Failure Assessment (SOFA) score (AUC = 0.878, 95% CI, 0.825-0.930) and quick Pitt Bacteremia Score (qPBS) (AUC = 0.897, 95% CI, 0.846-0.947). Calibration curve analysis and the Hosmer-Lemeshow (HL) test corroborate the concordance of our model with empirical observations. Furthermore, decision curve analysis (DCA) underscores the superior clinical utility of our predictive model when compared to the SOFA score and qPBS score. Most importantly, our results showed that PL is the most important predictor of in-hospital mortality in immunocompromised patients following severe infection.

Our findings highlight PL as the most significant predictor of in-hospital mortality in immunocompromised CKD patients. A clinical prediction model incorporating PL as a key variable exhibited robust performance in terms of diagnostic accuracy and clinical utility.

A shift toward a T cell exhaustion phenotype is associated with the upregulation of expression of programmed cell death protein 1 (PD-1) on T lymphocytes in patients with malignant solid tumors. The interaction between PD-1 and programmed death-ligand 1 (PD-L1) inhibits PD-1+ T lymphocyte function, impacting their anti-tumor immune activity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized the treatment of various solid malignancies, improving therapeutic efficacy and survival outcomes. Peripheral blood analysis of liquid biopsies is being increasingly used to identify populations most likely to benefit from various treatment modalities. PD-1+ T lymphocytes represent the primary cell population responsive to immunotherapeutic interventions for patients with solid malignancies, as evidenced by the altered PD-1 expression levels and proportion of cells comprising the overall population of immunocytes. PD-1+ T cells in peripheral blood exert an associative and reciprocal predictive effect on homologous intratumoral cells. Distinct subpopulations of PD-1+ T cells exhibit differential ability to proliferate in the periphery and can be characterized by tumor antigen-specific and exhaustion phenotypes. These characteristics have prognostic implications, aiding in the prediction of the efficacy of antitumor therapy and predicting survival outcomes. We highlight distinct subpopulations of PD-1+ T cells, their exhaustion and antigen-specific phenotypes, and their dynamic changes over treatment, providing insights into their utility for tailoring personalized therapies. For the first time, this review discusses the role of peripheral PD-1+ T lymphocytes as prognostic biomarkers in liquid biopsies, focusing on their clinical significance, predictive value during therapy, and future research directions.

Immune recognition and activation by the peptide-laden major histocompatibility complex-T cell receptor (TCR)-CD3 complex is essential for anti-tumor immunity. Tumors may escape immune surveillance by dissembling the complex. Here, we report that transferrin, which is overexpressed in patients with liver metastasis, disassociates TCR from the CD3 signaling apparatus by targeting the constant domain (CD) of T cell receptor α (TCRα), consequently suppresses T cell activation, and inhibits anti-metastatic and anti-tumor immunity. In mouse models of melanoma and lymphoma, transferrin overexpression exacerbates liver metastasis, while its knockdown, antibody, designed peptides, and CD mutation interfering with transferrin-TCRα interaction inhibit metastasis. This work reveals a novel strategy of tumor evasion of immune surveillance by blocking the coupling between TCRs and the CD3 signaling apparatus to suppress TCR activation. Given the conservation of CD and transferrin up-regulation in metastatic tumors, the strategy might be a common metastatic mechanism. Targeting transferrin-TCRα holds promise for anti-metastatic treatment.

Myocardial infarction (MI) is a prevalent cardiovascular disorder affecting individuals worldwide. There is a need to identify more effective therapeutic agents to minimize cardiomyocyte damage and enhance cardioprotection. Ginkgo biloba extract is extensively used to treat neurological disorders and peripheral vascular diseases. The aim of this study was to determine the protective effects and mechanisms of ginkgetin on postinfarction cardiomyocytes through bioinformatics and experimental validation.

Bioinformatics analysis was performed to predict the underlying biological mechanisms of ginkgetin in the treatment of MI. Next, we performed further validation through experiments. For in vivo studies, we used coronary ligation to construct an MI rat model. In vitro, oxygen and glucose deprivation (OGD) was performed to simulate ischemia in H9c2 cardiomyocytes.

Bioinformatics analysis revealed that the key targets of ginkgetin for MI treatment were MMP2, MMP9, and VEGFA. Immune infiltration analysis revealed that ginkgetin might be involved in immune regulation by acting on the TCR signaling pathway. The results of the GO enrichment analysis revealed that ginkgetin might protect the heart by acting on the cell membrane to alleviate the senescent apoptosis of cardiomyocytes after MI. In vivo studies revealed that ginkgetin ameliorated myocardial pathological damage and cardiac decompensation after MI. It also alleviated the inflammatory infiltration and senescent apoptosis of cardiomyocytes after MI. Additionally, ginkgetin can downregulate the activation signals of the TCR signaling pathway by dephosphorylating CD3 and CD28. In vitro studies revealed that ginkgetin attenuated elevated OGD-induced cytotoxicity, increased cell viability, and alleviated OGD-induced senescent apoptosis, thus protecting cardiomyocytes.

Ginkgetin inhibits postinfarction myocardial fibrosis and cardiomyocyte hypertrophy, scavenges oxygen free radicals, decreases postinfarction limbic cell inflammatory infiltration, suppresses activation of the inflammatory-immune pathway, and delays postinfarction peripheral cells from undergoing senescent apoptosis, thus protecting the heart.

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD-CD27- 'double-negative (DN)' DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.

Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism remains to be elucidated. Here, we investigated this issue using Wilson's disease (WD) as a model, which is a genetic disorder characterized by impaired mitochondrial function and copper metabolism. Our retrospective clinical study found that WD patients have a significantly higher incidence of cholecystitis and a poorer prognosis. The hepatic immune cell landscape using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in WD, mainly a major change in the constitution and function of the innate immune system. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by the upregulated expression of inhibitory receptors and the downregulated expression of cytotoxic molecules, which was verified in clinical samples. Further bioinformatic analysis confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated dysfunction of liver immune cells triggered by specific metabolic abnormalities in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis, providing new insights into the improvement of inflammatory diseases by assessing immune cell function.

The uridylation of 3'-RNA-a major process in epitranscriptomics- is catalyzed by terminal uridylyl transferases (TUTases), which are involved in multiple diseases and the immune response. Nonetheless, the role of TUTases in systemic lupus erythematosus (SLE) remains unknown. Here we identified increased level of MTPAP and ZCCHC6 and decreased level of PAPD5 and ZCCHC11 in SLE patients from Gene Expression Omnibus (GEO) GSE50772, GSE65391, and GSE121239. The random forest model was applied to screen 4 TUTase candidates (MTPAP, ZCCHC6, PAPD5, and ZCCHC11) to predict the susceptibility of SLE. A nomogram was constructed based on the 4 selected TUTase regulators. Decision curve analysis indicated that patients could benefit from the nomogram. Moreover, based on the 4 differentially expressed genes, individuals with SLE were divided into three patterns (Cluster A-C) using the consensus clustering method. Cluster B was enriched in adaptive immune cells, with the lowest TCE signature expression, manifesting a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) than that in Cluster A and C. whereas, Cluster C was enriched in innate immune cells, with the highest T-cell exhaustion (TCE) signature expression, manifesting lower SLEDAI than that in Cluster B. Clinically, lupus nephritis (LN) patients manifested increased expression of MTPAP and ZCCHC6 and decreased expression of PAPD5 and ZCCHC11 in PBMCs using Quantitative Polymerase Chain Reaction (q-PCR). Immunohistochemistry (IHC) illustrated higher level of ZCCHC6 in the kidneys of LN patients than that in NC. In summary, TUTases could predict the occurrence of SLE and stratify patients based on their immune characteristics, eventually predicting the disease activity and guiding immune therapy.

T cell exhaustion presents a major challenge for the efficacy of both immune checkpoint inhibitors (ICBs) and chimeric antigen receptor T (CAR-T) cell immunotherapies. To address this issue, we generate hypofunctional CAR-T cells that imitate the exhaustion state. By screening a Food and Drug Administration (FDA)-approved small molecule library using this model, we identify miltefosine as a potent molecule that restores the impaired function of CAR-T cells in a PD-1/PD-L1-independent manner. Impressively, in the terminally exhausted state where PD-1 antibody treatment is ineffective, miltefosine still enhances CAR-T cell activity. Single-cell sequencing analysis reveals that miltefosine treatment significantly increases the population of effector cells. Mechanistically, miltefosine improves impaired glycolysis and oxidative phosphorylation in hypofunctional CAR-T cells. In both allogeneic and syngeneic tumor models, miltefosine effectively enhances the solid tumor clearance ability of CAR-T cells and T cells, demonstrating its potential as an effective immunotherapeutic drug.

Major challenges of chimeric antigen receptor (CAR)-T cell therapy include poor antigen sensitivity and cell persistence. Here, we report a solution to these issues by exploiting CAR phase separation. We found that incorporation of an engineered T cell receptor CD3ε motif, EB6I, into the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. EB6I CAR formed a mature immunological synapse with the CD2 corolla to transduce efficient antigen and costimulatory signaling, although its tonic signaling remained low. Functionally, EB6I CAR-T cells exhibited improved signaling and cytotoxicity against low-antigen tumor cells and persistent tumor-killing function. In multiple primary and relapsed murine tumor models, EB6I CAR-T cells exerted better antitumor functions than conventional CAR-T cells against blood and solid cancers. This study thus unveils a CAR engineering strategy to improve CAR-T cell immunity by leveraging molecular condensation and signaling integration.

Chronic antigen exposure is frequently associated with T cell exhaustion. In a recent study, Aljobaily et al. show that pancreatic islet-infiltrating CD4+ T cells in mouse autoimmune diabetes may circumvent exhaustion by preserving TCF1 expression. Continuous recruitment of epigenetically pre-programmed CD62L+ CD4+ T cells seems to sustain the local autoimmune response.

Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.

CD8+ T cells play a critical role in specific immunity. In recent years, cell therapy has been emerging rapidly. The specific cytotoxic capabilities of these cells enable them to precisely identify and kill cells presenting specific antigens. This has demonstrated promise in the treatment of autoimmune diseases and cancers, with wide-ranging applications and value. However, in some diseases, such as tumors and chronic infections, T cells may adopt an exhausted phenotype, resulting in a loss of cytotoxicity and limiting their further application. Epigenetics plays a significant role in the differentiation and regulation of gene expression in cells. There is extensive evidence indicating that epigenetic remodeling plays an important role in T cell exhaustion. Therefore, further understanding its role in CD8+ T cell function can provide insights into the programmatic regulation of CD8+ T cells from a genetic perspective and overcome these diseases. We attempted to describe the relationship between the activation, function, and exhaustion mechanisms of CD8+ T cells, as well as epigenetics. This understanding makes it possible for us to address the aforementioned issues.

Transcriptomic analysis plays a vital role in investigating Systemic Lupus Erythematosus (SLE), a complex autoimmune disease characterized by diverse clinical manifestations. This approach has yielded valuable insights into gene expression patterns and molecular regulatory mechanisms involved in SLE pathogenesis. Notably, interferon-stimulated gene (ISG) signatures are significantly upregulated in immune cells, skin, and kidney. Although a correlation with serological parameters and clinical symptoms has been proposed, the association with global disease activities remains controversial. Key findings in the field include an upregulated plasmablast signature, which positively correlates with disease activity; a neutrophil signature associated with lupus nephritis; and a decreased lymphocyte signature, reflecting lymphopenia. Tissue-level studies highlight the critical role of infiltrating immune cells in organ damage. Future research should leverage advanced technologies and integrate multi-omics data to deepen our understanding of SLE's molecular underpinnings, facilitating the development of targeted therapies.

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease severity. The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can act as triggers. This review provides a comprehensive discussion of the pathogenesis and treatment strategies of SLE and focuses on the progress and status of traditional and emerging treatment strategies for SLE. Traditional treatment strategies for SLE have mainly employed non-specific approaches, including cytotoxic and immunosuppressive drugs, antimalarials, glucocorticoids, and NSAIDs. These strategies are effective in mitigating the effects of the disease, but they are not a complete cure and are often accompanied by adverse reactions. Emerging targeted therapeutic drugs, on the other hand, aim to control and treat SLE by targeting B and T cells, inhibiting their activation and function, as well as the abnormal activation of the immune system. A deeper understanding of the pathogenesis of SLE and the exploration of new targeted treatment strategies are essential to advance the treatment of this complex autoimmune disease.

Autoimmune diseases (ADs) are a collection of immunological disorders in which the immune system responds to self-antigens by producing autoantibodies or self-sensitized cells. Current treatments are unable to cure ADs, and achieving long-term drug-free remission remains a challenging task. Hematopoietic stem cell transplantation (HSCT) stands out from other therapies by specifically targeting ADs that target various cell subpopulations, demonstrating notable therapeutic benefits and resulting in sustained drug-free remission. Since different ADs have distinct mechanisms of action, the comprehensive understanding of how HSCT works in treating ADs is crucial. This review provides a detailed overview of the latest research and clinical applications of HSCT in treating ADs, offering new insights for clinicians aiming to optimize its use for ADs management.

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7- Tregs and CD226+CCR7-CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7- Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7- Tregs may inhibit CD226+CCR7-CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D.