Graphene Bilayer as a Template for Manufacturing Novel Encapsulated 2D Materials.

Bilayer graphene (BLG) has recently been used as a tool to stabilize encapsulated single sheets of various layered materials and tune their properties. It was also discovered that the protecting action of graphene sheets makes it possible to synthesize completely new two-dimensional materials (2DMs) inside the BLG by intercalating various atoms and molecules. In comparison to the bulk graphite, BLG allows for easier intercalation and a much larger increase in the interlayer separation of the sheets. Moreover, it enables studying the atomic structure of the intercalated 2DM by using high-resolution transmission electron microscopy. In this review, we summarize the recent progress in this area, with a special focus on new materials created inside BLG. We compare the experimental findings with the theoretical predictions, pay special attention to the discrepancies, and outline the challenges in the field. Finally, we discuss unique opportunities offered by intercalation into 2DMs beyond graphene and their heterostructures.

Comprehensive genomic profiling in multiple cancer types: A comparative analysis of the National Biobank Consortium of Taiwan and clinical practice cohorts.

BACKGROUND: This retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors. MATERIAL AND METHODS: Patients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification. RESULTS: FoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7-35.5 months) and 10.6 months (95% CI, 8.1-13.1 months; hazard ratio, 0.28, 95% CI, 0.14-0.55, p < 0.001), respectively. CONCLUSIONS: This study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice.

Crossover between rigid and reconstructed moiré lattice in h-BN-encapsulated twisted bilayer WSe2 with different twist angles.

A moiré lattice in a twisted-bilayer transition metal dichalcogenide (tBL-TMD) exhibits a complex atomic reconstruction effect when its twist angle is less than a few degrees. The influence of the atomic reconstruction on material properties of the tBL-TMD has been of particular interest. In this study, we performed scanning transmission electron microscopy (STEM) imaging of a moiré lattice in h-BN-encapsulated twisted bilayer WSe2 with various twist angles. Atomic-resolution imaging of the moiré lattice revealed a reconstructed moiré lattice below a crossover twist angle of ∼4° and a rigid moiré lattice above this angle. Our findings indicate that h-BN encapsulation has a considerable influence on lattice reconstruction, as the crossover twist angle was larger in h-BN-encapsulated devices compared to non-encapsulated devices. We believe that this difference is due to the improved flatness and uniformity of the twisted bilayers with h-BN encapsulation. Our results provide a foundation for a deeper understanding of the lattice reconstruction in twisted TMD materials with h-BN encapsulation.

Superatomic Layer of Cubic Mo4S4 Clusters Connected by Cl Cross-Linking.

Superatomic clusters - assemblies of atoms with various sizes, shapes, and compositions - can form hierarchical architectures that exhibit emergent electronic properties not found in their individual units. In particular, cubic M4X4 clusters of chalcogenides (M = transition metal; X = chalcogen) are recognized as versatile building blocks for 3D structures with tunable morphologies and electronic properties. However, tetrahedral M4X4 clusters rarely assemble into 2D architectures, which could offer a distinct class of functional materials from their 3D analogues. Here, this work reports the preparation of 2D Mo8S8Cl11, a superatomic layer with a sandwich structure consisting of Mo4S4 clusters interconnected through Cl cross-linking. The vapor-phase reaction inside nanotubes promotes the selective growth of Mo8S8Cl11 nanoribbons, allowing detailed characterization via transmission electron microscopy. This methodology can be applied to the growth of layered structures containing Mo8S8Cl11 at the micrometer scale. This work has demonstrated that mono- and few-layer Mo8S8Cl11 can be prepared by exfoliation of parent solids. Electronic structure calculations indicate that the 2D monolayer has quasi-flat bands, giving rise to an indirect-to-direct bandgap transition under mechanical strain. Furthermore, scanning electrochemical microscopy reveals the potential of the layered structures as highly efficient catalysts for the hydrogen-evolution reaction.

Synthesis of Few-Layer Hexagonal Boron Nitride for Magnetic Tunnel Junction Application.

Hexagonal boron nitride (hBN), a wide-gap two-dimensional (2D) insulator, is an ideal tunneling barrier for many applications because of the atomically flat surface, high crystalline quality, and high stability. Few-layer hBN with a thickness of 1-2 nm is an effective barrier for electron tunneling, but the preparation of few-layer hBN relies on mechanical exfoliation from bulk hBN crystals. Here, we report the large-area growth of few-layer hBN by chemical vapor deposition on ferromagnetic Ni-Fe thin films and its application to tunnel barriers of magnetic tunnel junction (MTJ) devices. Few-layer hBN sheets mainly consisting of two to three layers have been successfully synthesized on a Ni-Fe catalyst at a high growth temperature of 1200 °C. The MTJ devices were fabricated on as-grown hBN by using the Ni-Fe film as the bottom ferromagnetic electrode to avoid contamination and surface oxidation. We found that trilayer hBN gives a higher tunneling magnetoresistance (TMR) ratio than bilayer hBN, resulting in a high TMR ratio up to 10% at ∼10 K.

Safety, Efficacy, and Pharmacokinetics of SHR-A1811, a Human Epidermal Growth Factor Receptor 2-Directed Antibody-Drug Conjugate, in Human Epidermal Growth Factor Receptor 2-Expressing or Mutated Advanced Solid Tumors: A Global Phase I Trial.

PURPOSE: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors. METHODS: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose. RESULTS: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors. CONCLUSION: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

Clinical characteristics and genetic HLA marker for patients with oxaliplatin-induced adverse drug reactions.

BACKGROUND: Oxaliplatin is commonly used to treat gastrointestinal malignancies. However, its applications are limited due to potential adverse drug reactions (ADRs), particularly severe anaphylactic shock. There is no method to predict or prevent ADRs caused by oxaliplatin. Therefore, we aimed to investigate the genetic HLA predisposition and immune mechanism of oxaliplatin-induced ADRs. METHODS: A retrospective review was performed for 154 patients with ADRs induced by oxaliplatin during 2016-2021 recorded in our ADR notification system. HLA genotyping was conducted for 47 patients with oxaliplatin-induced ADRs, 1100 general population controls, and 34 oxaliplatin-tolerant controls in 2019-2023. The in vitro basophil activation test (BAT) was performed and oxaliplatin-specific IgE levels were determined. RESULTS: The incidence of oxaliplatin-induced ADRs and anaphylactic shock in our cohort was 7.1% and 0.15%, respectively. Of the 154 patients, 67.5% suffered rash/eruption; 26.0% of the patients who could not undergo oxaliplatin rechallenge were considered to show oxaliplatin-induced immune-mediated hypersensitivity reactions (HRs). The genetic study found that the HLA-DRB∗12:01 allele was associated with oxaliplatin-induced HRs compared to the general population controls (sensitivity = 42.9%; odds ratio [OR] = 3.4; 95% CI = 1.4-8.2; P = 0.008) and tolerant controls (OR = 12; 95% CI = 2.3-63.7; P = 0.001). The in vitro BAT showed higher activation of CD63+ basophils in patients with oxaliplatin-induced HRs compared to the tolerant controls (P < 0.05). Only four patients (8.5%) with oxaliplatin-induced ADRs were positive for oxaliplatin-specific IgE. CONCLUSIONS: This study found that 26.0% of patients with oxaliplatin-induced ADRs could not undergo oxaliplatin rechallenge. HLA-DRB∗12:01 is regarded as a genetic marker for oxaliplatin-induced hypersensitivity.

Factors Influencing Health Promotion Lifestyle in Female Breast Cancer Survivors: The Role of Health Behavior Self-Efficacy and Associated Factors.

OBJECTIVES: To examine the factors influencing health-promoting lifestyles and the changes in health behavior self-efficacy and health-promoting lifestyles among female breast cancer survivors over a 6-month period. METHODS: A longitudinal design with purposive sampling was deployed. Data collection occurred at the baseline (T1), 3 months (T2), and 6 months (T3). In total, 53 breast cancer survivors agreed to participate. All participants completed the first two rounds of data collection, 49 participants completed data collection at the 6-month mark (T3). The Chinese versions of the Self-Rated Abilities for Health Practices Scale (SRAHP) and the Health-Promoting Lifestyle Profile (HPLP) were used. RESULTS: Health behavior self-efficacy and health-promoting lifestyle scores increased over time. Age, impaired cardiac function, those taking a career break, psychological well-being, and responsible health practice in self-efficacy for health behaviors were significant predictors of health-promoting lifestyle. CONCLUSIONS: Younger breast cancer survivors, those taking a career break, and those with poor health behavior self-efficacy were less likely to engage in a health-promoting lifestyle and may require guidance in improving overall health behaviors. IMPLICATIONS FOR NURSING PRACTICE: Healthcare providers should not only be aware of the suboptimal health promotion lifestyle in breast cancer survivors but also focus on enhancing health behavior self-efficacy. This is particularly crucial for younger breast cancer survivors or those currently unemployed.

Alkali metal bilayer intercalation in graphene.

Alkali metal (AM) intercalation between graphene layers holds promise for electronic manipulation and energy storage, yet the underlying mechanism remains challenging to fully comprehend despite extensive research. In this study, we employ low-voltage scanning transmission electron microscopy (LV-STEM) to visualize the atomic structure of intercalated AMs (potassium, rubidium, and cesium) in bilayer graphene (BLG). Our findings reveal that the intercalated AMs adopt bilayer structures with hcp stacking, and specifically a C6M2C6 composition. These structures closely resemble the bilayer form of fcc (111) structure observed in AMs under high-pressure conditions. A negative charge transferred from bilayer AMs to graphene layers of approximately 1~1.5×1014 e-/cm-2 was determined by electron energy loss spectroscopy (EELS), Raman, and electrical transport. The bilayer AM is stable in BLG and graphite superficial layers but absent in the graphite interior, primarily dominated by single-layer AM intercalation. This hints at enhancing AM intercalation capacity by thinning the graphite material.

Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.

Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development. SIGNIFICANCE: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5.

The influence of chronic renal insufficiency on multi-therapeutic modalities for breast cancer: a single-center experience.

BACKGROUND: Due to the presence of other comorbidities and multi-therapeutic modalities in breast cancer, renally cleared chemotherapeutic regimens may cause nephrotoxicity. The aim of this retrospective study is to compare the chemotherapy types and outcomes in breast cancer patients with or without chronic renal disease. PATIENTS AND METHODS: We retrospectively enrolled 62 female patients with breast cancer and underlying late stages (stage 3b, 4, and 5) of chronic kidney disease (CKD) treated from 2000 to 2017. They were propensity score-matched 1:1 with patients in our database with breast cancer and normal renal function (total n = 124). RESULTS: The main subtype of breast cancer was luminal A and relatively few patients with renal impairment received chemotherapy and anti-Her-2 treatment. The breast cancer patients with late-stage CKD had a slightly higher recurrent rate, especially at the locally advanced stage. The 5-year overall survival was 90.1 and 71.2% for patients without and with late-stage CKD, but the breast cancer-related mortality rate was 88.9 and 24.1%, respectively. In multivariate analyses, dose-reduced chemotherapy was an independent negative predictor of 5-year recurrence-free survival and late-stage CKD was associated with lower 5-year overall survival rate. CONCLUSIONS: Breast cancer patients with late-stage CKD may receive insufficient therapeutic modalities. Although the recurrence-free survival rate did not differ significantly by the status of CKD, patients with breast cancer and late-stage CKD had shorter overall survival time but a lower breast cancer-related mortality rate, indicated that the mortality was related to underlying disease.

Excitonic Effects in Energy-Loss Spectra of Freestanding Graphene.

In this work, we perform electron energy-loss spectroscopy (EELS) of freestanding graphene with high energy and momentum resolution to disentangle the quasielastic scattering from the excitation gap of Dirac electrons close to the optical limit. We show the importance of many-body effects on electronic excitations at finite transferred momentum by comparing measured EELS to ab initio calculations at increasing levels of theory. Quasi-particle corrections and excitonic effects are addressed within the GW approximation and the Bethe-Salpeter equation, respectively. Both effects are essential in the description of the EEL spectra to obtain a quantitative agreement with experiments, with the position, dispersion, and shape of both the excitation gap and the π plasmon being significantly affected by excitonic effects.

Molybdenum Chloride Nanostructures with Giant Lattice Distortions Intercalated into Bilayer Graphene.

The nanospace of the van der Waals (vdW) gap between structural units of two-dimensional (2D) materials serves as a platform for growing unusual 2D systems through intercalation and studying their properties. Various kinds of metal chlorides have previously been intercalated for tuning the properties of host layered materials, but the atomic structure of the intercalants remains still unidentified. In this study, we investigate the atomic structural transformation of molybdenum(V) chloride (MoCl5) after intercalation into bilayer graphene (BLG). Using scanning transmission electron microscopy, we found that the intercalated material represents MoCl3 networks, MoCl2 chains, and Mo5Cl10 rings. Giant lattice distortions and frequent structural transitions occur in the 2D MoClx that have never been observed in metal chloride systems. The trend of symmetric to nonsymmetric structural transformations can cause additional charge transfer from BLG to the intercalated MoClx, as suggested by our density functional theory calculations. Our study deepens the understanding of the behavior of matter in the confined space of the vdW gap in BLG and provides hints at a more efficient tuning of material properties by intercalation for potential applications, including transparent conductive films, optoelectronics, and energy storage.

Direct Observation of Locally Modified Excitonic Effects within a Moiré Unit Cell in Twisted Bilayer Graphene.

Bilayer graphene, which forms moiré superlattices, possesses distinct electronic and optical properties owing to its hybridized energy band and the emergence of van Hove singularities depending on its twist angle. Extensive research has been conducted on the global characteristics of moiré superlattices induced by their long-range periodicity. However, the local properties, which differ owing to the variations in the three-dimensional atomic arrangement, within a moiré unit cell have been rarely explored. In this study, we demonstrate the highly localized excitation of carbon 1s electrons to unoccupied van Hove singularities in twisted bilayer graphene by electron energy loss spectroscopy using a monochromated transmission electron microscope. The core-level excitations associated with the van Hove singularities exhibit a systematic twist-angle dependence analogous to optical excitations. Furthermore, local variations in the core-level van Hove singularity peaks, which can originate from the core-exciton lifetimes and band modifications corresponding to the local stacking geometry within a moiré unit cell, are unambiguously corroborated.

An IL-17-EGFR-TRAF4 axis contributes to the alleviation of lung inflammation in severe influenza.

Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naïve hemagglutinin-specific CD4+ T cells from CD4+ TCR-transgenic 6.5 mice drive an IFN-γ-producing Th1 response in wild-type mice. It helps in virus clearance but also causes collateral damage and disease aggravation. The donor 6.5 mice have all the CD4+ T cells with TCR specificity toward influenza hemagglutinin. Still, the infected 6.5 mice do not suffer from robust inflammation and grave outcome. The initial Th1 response wanes with time, and a prominent Th17 response of recent thymic emigrants alleviates inflammation and bestows protection in 6.5 mice. Our results suggest that viral neuraminidase-activated TGF-ß of the Th1 cells guides the Th17 evolution, and IL-17 signaling through the non-canonical IL-17 receptor EGFR activates the scaffold protein TRAF4 more than TRAF6 during alleviation of lung inflammation in severe influenza.

Murine cytotoxic CD4+ T cells in the tumor microenvironment are at a hyper-maturation stage of Th1 CD4+ T cells sustained by IL-12.

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.

Vapor-Phase Indium Intercalation in van der Waals Nanofibers of Atomically Thin W6Te6 Wires.

One-dimensional (1D) conducting materials are of great interest as potential building blocks for integrated nanocircuits. Ternary 1D transition-metal chalcogenides, consisting of M6X6 wires with intercalated A atoms (M = Mo or W; X = S, Se, or Te; A = alkali or rare metals, etc.), have attracted much attention due to their 1D metallic behavior, superconductivity, and mechanical flexibility. However, the conventional solid-state reaction usually produces micrometer-scale bulk crystals, limiting their potential use as nanoscale conductors. Here we demonstrate a versatile method to fabricate indium (In)-intercalated W6Te6 (In-W6Te6) bundles with a nanoscale thickness. We first prepared micrometer-long, crystalline bundles of van der Waals W6Te6 wires using chemical vapor deposition and intercalated In into the crystal via a vapor-phase reaction. Atomic-resolution electron microscopy revealed that In atoms were surrounded by three adjacent W6Te6 wires. First-principles calculations suggested that their wire-by-wire stacking can transform through postgrowth intercalation. Individual In-W6Te6 bundles exhibited metallic behavior, as theoretically predicted. We further identified the vibrational modes by combining polarized Raman spectroscopy and nonresonant Raman calculations.

Immunophenotype and antitumor activity of cytokine-induced killer cells from patients with hepatocellular carcinoma.

BACKGROUND: Cytokine-induced killer (CIK) cells are heterogeneous lymphocytes from human peripheral blood mononucleated cells (PBMCs) co-cultured with several cytokines. The main purpose of this study is to evaluate the functional characteristics and anticancer ability of CIK cells from hepatocarcinoma (HCC) patients. METHODS: CIK cells were activated ex-vivo and expanded from PBMCs from HCC patients. The immunophenotype and the ex-vivo killing ability of CIK cells were evaluated. Human CIK cells were intravenously injected into NOD/SCID mice to evaluate the in vivo anticancer ability. RESULTS: More than 70% of CIK cells were CD3+CD8+, and 15%-30% were CD3+CD56+. These cells expressed an increased number of activated natural killer (NK) receptors, such as DNAM1 and NKG2D, and expressed low-immune checkpoint molecules, including PD-1, CTLA-4, and LAG-3. Among the chemokine receptors expressed by CIKs, CXCR3 and CD62L were elevated in CD8+ T cells, representing the trafficking ability to inflamed tumor sites. CIK cells possess the ex-vivo anticancer activity to different cell lines. To demonstrate in vivo antitumor ability, human CIK cells could significantly suppress the tumor of J7 bearing NOD/SCID mice. Furthermore, human immune cells could be detected in the peripheral blood and on the tumors after CIK injection. CONCLUSIONS: This study revealed that CIK cells from HCC patients possess cytotoxic properties, and express increased levels of effector NK receptors and chemokine molecules and lower levels of suppressive checkpoint receptors. CIK cells can suppress human HCC ex-vivo and in vivo. Future clinical trials of human CIK cell therapy for HCC are warranted.

The origin of regulatory from the effector cells in LAG-3-marked Th1 immunity against severe influenza virus infection.

In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad-spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen-specific transgenic mouse experimental model, step-wise evolving cells from a pool of naïve hemagglutinin-specific CD4+ T cells were studied for phenotypic, genomic, and functional characterization in vivo. Naïve CD4+ T cells respond with Th1 commitment in the absolute majority. They first develop into LAG-3Med IFN-γ-secreting Th1 effectors and then evolve into LAG-3High IFN-γ-not-secreting regulators with increasing LAG-3 expression upon continuous activation and cell division. The LAG-3Med IFN-γ-secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen-specific CD8+ T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG-3High regulators do not contribute to inflammation, suppress CD8+ T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8+ T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp-3+ regulator-mediated suppression, which suppresses proliferative and inflammatory responses of the CD8+ T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG-3-marked Th1 immunity alleviates lung inflammation without impairment of virus eradication.