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COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild, and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.

T follicular helper (T FH ) cells are specialized effector CD4 + T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in T FH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N 6 -methyladenosine (m 6 A) modification) in CD4 + T cells impairs T FH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important T FH signature genes, including Tcf7 , Bcl6 , Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m 6 A-miCLIP-seq shows the 3′ UTR of Tcf7 mRNA is subjected to METTL3-dependent m 6 A modification. Loss of METTL3 or mutation of the Tcf7 3′ UTR m 6 A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7 ) rectifies T FH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m 6 A modification to ensure activation of a T FH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting T FH cell differentiation. T follicular helper (T FH ) cells are specialized effector CD4 + T cells that are critical in humoral immunity, but the function of post-transcriptional regulation is not clearly defined. Here, the authors demonstrate that RNA methylation is important for T FH effector differentiation and subsequent antibody formation through stabilization of Tcf7 transcripts.

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3β kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2–AKT–GSK3β axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.Wang et al. show that the Rictor-dependent mTORC2–Akt pathway is needed to maintain CD4+ memory cells. This axis acts, in part, by suppressing mitoROS generation and subsequent oxidation of membrane phospholipids, which then triggers cell death by ferroptosis.

Follicular helper T cells (T FH cells) require the transcription factor Bcl-6 and are antagonized by the transcription factor Blimp1 (encoded by Prdm1 ). Lilin Ye and colleagues show that acute viral infection induces the transcription factor TCF-1, which promotes T FH differentiation by enhancing Bcl6 expression while suppressing that of Prdm1 . Induction of the transcriptional repressor Bcl-6 in CD4 + T cells is critical for the differentiation of follicular helper T cells (T FH cells), which are essential for B cell–mediated immunity. In contrast, the transcription factor Blimp1 (encoded by Prdm1 ) inhibits T FH differentiation by antagonizing Bcl-6. Here we found that the transcription factor TCF-1 was essential for both the initiation of T FH differentiation and the effector function of differentiated T FH cells during acute viral infection. Mechanistically, TCF-1 bound directly to the Bcl6 promoter and Prdm1 5′ regulatory regions, which promoted Bcl-6 expression but repressed Blimp1 expression. TCF-1-null T FH cells upregulated genes associated with non-T FH cell lineages. Thus, TCF-1 functions as an important hub upstream of the Bcl-6–Blimp1 axis to initiate and secure the differentiation of T FH cells during acute viral infection.

IntroductionIntensive care unit-acquired weakness (ICUAW) is a common and severe complication in critically ill patients, associated with high morbidity and poor prognosis. Despite increasing focus on ICUAW, definitive diagnostic and therapeutic strategies remain absent. Early mobilisation has been demonstrated as an effective intervention for preventing and alleviating ICUAW. This study aims to evaluate the early-stage efficacy of suspended lower-limb rehabilitation robot-assisted therapy in patients with ICUAW.Methods and analysisThis study is a self-controlled randomised trial aiming to include 60 patients with ICUAW. Each patient’s lower limbs will be randomly assigned to either the experimental group or the control group. The control group will receive standard rehabilitation therapy, while the experimental group will receive additional suspended lower-limb rehabilitation robot-assisted therapy alongside standard care. The intervention will be delivered for 40 min daily, 5 days per week, over a 2-week period. The primary outcome measure is the thickness of key lower-limb muscles assessed via musculoskeletal ultrasound. Secondary outcome measures include the Medical Research Council score, range of motion of the lower-limb joints, and limb circumference. Data will be collected at baseline, after 1 week of intervention and at the 2-week endpoint.Ethics and disseminationThis study has received ethical approval from the Research Ethics Committee of Changhai Hospital, affiliated with the Naval Medical University (approval reference: CHEC2023-055). Written informed consent will be obtained from all participants prior to their inclusion in the study. The findings, including both positive and negative outcomes, will be disseminated through publication in international peer-reviewed journals and presentation at relevant academic conferences.Trial registration numberChiCTR2300070118.

IntroductionColonoscopy is an essential procedure for the early diagnosis of colorectal conditions; however, over 60% of patients undergoing non-sedated colonoscopy report moderate to severe pain. This study aims to investigate the central analgesic mechanisms of transcutaneous electrical nerve stimulation based on wrist-ankle acupuncture theory (TENS-WAA). A multimodal approach combining electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) will be employed to assess pain-related brain activity, with artificial intelligence applied to model the relationship between objective neurophysiological signals and subjective pain experience.MethodsThis is a single-centre, randomised, double-blind, controlled trial involving 60 patients undergoing colonoscopy without anaesthesia. Participants will be randomly allocated (1:1) to either an electrical stimulation group receiving TENS-WAA or a sham stimulation group. EEG and fNIRS data will be acquired before, during and after the procedure. The primary outcome is the analysis of EEG-fNIRS signals to characterise cerebral responses associated with pain modulation. Secondary outcomes include patient-reported pain using the Visual Analogue Scale (VAS), total colonoscopy duration and the correlation between EEG-fNIRS indicators and VAS scores. A deep learning framework will be used to enhance pain prediction accuracy.Ethics and disseminationThis study has received ethical approval from the Ethics Committee of Changhai Hospital, Shanghai (approval reference CHEC2025-006), and has been registered at ClinicalTrials.gov. Written informed consent will be obtained from all participants. Findings will be disseminated in peer-reviewed academic journals and at relevant scientific conferences, regardless of outcome, contributing to evidence-based, non-pharmacological pain management strategies.Trial registration numberClinicalTrials.gov, NCT06813703.

Periampullary carcinoma is a malignant gastrointestinal tumor originating from the head of the pancreas, distal bile duct, duodenum, or the ampulla of Vater. Currently, surgery remains the primary treatment option, yet the postoperative recurrence rate remains high. Chemotherapy is the main approach for controlling postoperative recurrence. Histologically, periampullary carcinoma is categorized into two types: intestinal (IN) and pancreaticobiliary (PB) subtype. Each subtype requires different therapeutic approaches, with the PB type primarily treated with gemcitabine and the IN type with 5-FU. Despite these options, patient outcomes are still unsatisfactory. In recent years, the feasibility of immunotherapy in tumor treatment has been increasingly evidenced, although research on its efficacy in periampullary carcinoma treatment is still limited. In this report, we present a case of a periampullary carcinoma patient who experienced recurrence and metastasis after undergoing radical pancreatoduodenectomy and receiving gemcitabine-based chemotherapy post-surgery. Through next-generation sequencing (NGS), we identified high expression levels of programmed cell death-ligand 1 (PD-L1) with a combined positive score (CPS) of 35, high tumor mutation burden (TMB-H), and high microsatellite instability (MSI-H) in this patient. Therefore, we implemented a combination therapy using Tislelizumab and chemotherapy. According to the latest follow-up, the tumors are effectively controlled. Our utilization of immunotherapy combined with chemotherapy holds significant implication for the treatment of periampullary carcinoma.

Epigenetic modifications to histones dictate the differentiation of naïve CD4+ T cells into different subsets of effector T helper (TH) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of TH1, TH2 and regulatory T (Treg) cells. However, whether and how EZH2 regulates follicular helper T (TFH) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells. Ablation of EZH2 in LCMV-specific CD4+ T cells leads to a selective impairment of early TFH cell fate commitment, but not late TFH differentiation or memory TFH maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs TFH cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.

BackgroundAntitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+ T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8+ T-cell epitopes can drive the functional exhaustion of tumor-specific CD8+ T cells. Tumor-specific type-I helper CD4+ T (TH1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8+ T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4+ T-cell epitopes to induce tumor-specific TH1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.MethodsListeria monocytogenes vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-restricted CD4+ T cell epitope (GP61–80) or ovalbumin-specific CD4+ T cell epitope (OVA323-339) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4+ T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing.ResultsCD4+ T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8+ T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8+ T cells.ConclusionCD4+ T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.