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Redox flow batteries are experiencing rapid growth for stationary energy‐storage applications. To satisfy the demand for wider applications, however, improved energy density of redox flow batteries is desperately required. Past and present efforts to increase the energy density are briefly surveyed herein and several strategies are explored. Go with the flow: The latest advances in redox flow battery (RFB) related technologies are highlighted in the context of a few decades of development. The technology has mainly advanced through a process of enlarging the electrochemical window by using organic solvents and replacing liquid electrolytes with solid or semisolid materials (see picture).

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.

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.

ABSTRACT CD8+ tissue‐resident memory T cells (TRM) are strategically located in peripheral tissues, enabling a rapid response to local infections, which is different from circulating memory CD8+ T cells. Their unique positioning makes them promising targets for vaccines designed to enhance protection at barrier sites and other organs. Recent studies have shown a correlation between CD8+ TRM cells and favorable clinical outcomes in various types of cancer, indicating their potential role in immune checkpoint blockade (ICB) therapies. However, the dual nature of CD8+ TRM cells presents challenges, as their inappropriate activation may lead to autoimmunity and chronic inflammatory conditions. This review highlights significant advancements in the field, focusing on the differentiation pathways and phenotypic heterogeneity of CD8+ TRM cells across different tissues and disease states. We also review their protective roles in various contexts and the implications for vaccine development against infections and treatment strategies for tumors. Overall, this comprehensive review outlines the common features of CD8+ TRM cell differentiation and biological functions, emphasizing their specific characteristics across diverse tissues and disease states, which can guide the design of therapies against infections and tumors while minimizing the risk of autoimmune diseases. Xu et al. described the differentiation, biological function, and phenotype heterogeneity of CD8+TRM cells across various types of tissues and distinct disease settings, and discussed their potential roles in the designation of vaccines against infectious diseases and immune therapy of tumors .

During viral infection, virus-specific follicular helper T cells provide important help to cognate B cells for their survival, consecutive proliferation and mutation and eventual differentiation into memory B cells and antibody-secreting plasma cells. Similar to Tfh cells generated in other conditions, the differentiation of virus-specific Tfh cells can also be characterized as a process involved multiple factors and stages, however, which also exhibits distinct features. Here, we mainly focus on the current understanding of Tfh fate commitment, functional maturation, lineage maintenance and memory transition and formation in the context of viral infection.

The long-term persistence of viral antigens drives virus-specific CD8 T cell exhaustion during chronic viral infection. Yet exhausted, CD8 T cells are still endowed with certain levels of effector function, by which they can keep viral replication in check in chronic infection. However, the regulatory factors involved in regulating the effector function of exhausted CD8 T cell are largely unknown. Using mouse model of chronic LCMV infection, we found that the deletion of transcription factor TCF-1 in LCMV-specific exhausted CD8 T cells led to the profound reduction in cytokine production and degranulation. Conversely, ectopic expression of TCF-1 or using agonist to activate TCF-1 activities promotes the effector function of exhausted CD8 T cells. Mechanistically, TCF-1 fuels the functionalities of exhausted CD8 T cells by promoting the expression of an array of key effector function-associated transcription regulators, including Foxo1, Zeb2, Id3, and Eomes. These results collectively indicate that targeting TCF-1 mediated transcriptional pathway may represent a promising immunotherapy strategy against chronic viral infections by reinvigorating the effector function of exhausted virus-specific CD8 T cells.

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.

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n  = 10, moderate, n  = 32, severe, n  = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (T FH ) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific T H 1 and CD8 + T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated T FH responses; however, the virus-specific T H 1 and CD8 + T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.