The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8+ T cell fates.

Antigen-experienced CD8+ T cells form effector and central memory T cells (TEM and TCM cells, respectively); however, the mechanism(s) controlling their lineage plasticity remains incompletely understood. Here we show that the transcription cofactor Tle3 critically regulates TEM and TCM cell fates and lineage stability through dynamic redistribution in antigen-responding CD8+ T cell genome. Genetic ablation of Tle3 promoted CD8+ TCM cell formation at the expense of CD8+ TEM cells. Lineage tracing showed that Tle3-deficient CD8+ TEM cells underwent accelerated conversion into CD8+ TCM cells while retaining robust recall capacity. Tle3 acted as a coactivator for Tbet to increase chromatin opening at CD8+ TEM cell-characteristic sites and to activate CD8+ TEM cell signature gene transcription, while engaging Runx3 and Tcf1 to limit CD8+ TCM cell-characteristic molecular features. Thus, Tle3 integrated functions of multiple transcription factors to guard lineage fidelity of CD8+ TEM cells, and manipulation of Tle3 activity could favor CD8+ TCM cell production.

Tcf1-CTCF cooperativity shapes genomic architecture to promote CD8+ T cell homeostasis.

CD8+ T cell homeostasis is maintained by the cytokines IL-7 and IL-15. Here we show that transcription factors Tcf1 and Lef1 were intrinsically required for homeostatic proliferation of CD8+ T cells. Multiomics analyses showed that Tcf1 recruited the genome organizer CTCF and that homeostatic cytokines induced Tcf1-dependent CTCF redistribution in the CD8+ T cell genome. Hi-C coupled with network analyses indicated that Tcf1 and CTCF acted cooperatively to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8+ T cells before and after cytokine stimulation. Ablating CTCF phenocopied the proliferative defects caused by Tcf1 and Lef1 deficiency. Tcf1 and CTCF controlled a similar set of genes that regulated cell cycle progression and promoted CD8+ T cell homeostatic proliferation in vivo. These findings identified CTCF as a Tcf1 cofactor and uncovered an intricate interplay between Tcf1 and CTCF that modulates the genomic architecture of CD8+ T cells to preserve homeostasis.

Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses.

The mechanisms underlying the heightened protection mediated by central memory CD8+ T (TCM) cells remain unclear. Here we show that the transcription factor Tcf1 was required in resting TCM cells to generate secondary effector CD8+ T cells and to clear pathogens during recall responses. Recall stimulation of CD8+ TCM cells caused extensive reprogramming of the transcriptome and chromatin accessibility, leading to rapid induction of glycolytic enzymes, cell cycle regulators and transcriptional regulators, including Id3. This cluster of genes did not require Tcf1 in resting CD8+ TCM cells, but depended on Tcf1 for optimal induction and chromatin opening in recall-stimulated CD8+ TCM cells. Tcf1 bound extensively to these recall-induced gene loci in resting CD8+ TCM cells and mediated chromatin interactions that positioned these genes in architectural proximity with poised enhancers. Thus, Tcf1 preprogramed a transcriptional program that supported the bioenergetic and proliferative needs of CD8+ TCM cells in case of a secondary challenge.

Antigen exposure reshapes chromatin architecture in central memory CD8+ T cells and imprints enhanced recall capacity.

CD62L+ central memory CD8+ T (TCM) cells provide enhanced protection than naive cells; however, the underlying mechanism, especially the contribution of higher-order genomic organization, remains unclear. Systematic Hi-C analyses reveal that antigen-experienced CD8+ T cells undergo extensive rewiring of chromatin interactions (ChrInt), with TCM cells harboring specific interaction hubs compared with naive CD8+ T cells, as observed at cytotoxic effector genes such as Ifng and Tbx21. TCM cells also acquire de novo CTCF (CCCTC-binding factor) binding sites, which are not only strongly associated with TCM-specific hubs but also linked to increased activities of local gene promoters and enhancers. Specific ablation of CTCF in TCM cells impairs rapid induction of genes in cytotoxic program, energy supplies, transcription, and translation by recall stimulation. Therefore, acquisition of CTCF binding and ChrInt hubs by TCM cells serves as a chromatin architectural basis for their transcriptomic dynamics in primary response and for imprinting the code of "recall readiness" against secondary challenge.

The Interplay of Transcription and Genome Topology Programs T Cell Development and Differentiation.

T cells are essential for mounting defense against various pathogens and malignantly transformed cells. Thymic development and peripheral T cell differentiation are highly orchestrated biological processes that require precise gene regulation. Higher-order genome organization on multiple scales, in the form of chromatin loops, topologically associating domains and compartments, provides pivotal control of T cell gene expression. CTCF and the cohesin machinery are ubiquitously expressed architectural proteins responsible for establishing chromatin structures. Recent studies indicate that transcription factors, such as T lineage-defining Tcf1 and TCR-induced Batf, may have intrinsic ability and/or engage CTCF to shape chromatin architecture. In this article, we summarize current knowledge on the dynamic changes in genome topology that underlie normal or leukemic T cell development, CD4+ helper T cell differentiation, and CD8+ cytotoxic T cell functions. The knowledge lays a solid foundation for elucidating the causative link of spatial chromatin configuration to transcriptional and functional output in T cells.

Co-doped NaYF4:Yb/Er/Tm upconversion luminescent coating to enhance the efficiency of photovoltaic cells.

The use of upconversion luminescent materials to broaden the utilization range of the solar spectrum to enhance the efficiency of photovoltaic cells offers a promising and sustainable approach. However, the low luminescence intensity and easy quenching of upconversion luminescent materials bring serious challenges to the practical application. Herein, a novel method using Co2+ ion doping to regulate the luminescence properties of NaYF4:Yb/Er/Tm is proposed. NaYF4:Yb/Er/Tm microcrystals doped with different proportions of Co2+ ions are prepared and used as coatings on the surface of photovoltaic cells. Co2+ ions regulate the crystallinity and size of the NaYF4:Yb/Er/Tm microcrystals and reduce the crystal field symmetry of the activator (Er3+ and Tm3+) ions. The results show that the emission intensity of green and red light is 18.19% and 83.24% times higher than that of undoped Co2+ ion materials, respectively. Besides, the efficiency of photovoltaic cells after coating Co2+ ion doped NaYF4:Yb/Er/Tm is 2.08% higher than that of the uncoated one. This work underscores the importance of Co2+ ion doping to improve and enhance the luminescence properties of NaYF4:Yb/Er/Tm, to further enhance the efficiency of photovoltaic cells.

Artificial Intelligence in Chronic Obstructive Pulmonary Disease: Research Status, Trends, and Future Directions --A Bibliometric Analysis from 2009 to 2023.

Objective: A bibliometric analysis was conducted using VOSviewer and CiteSpace to examine studies published between 2009 and 2023 on the utilization of artificial intelligence (AI) in chronic obstructive pulmonary disease (COPD). Methods: On March 24, 2024, a computer search was conducted on the Web of Science (WOS) core collection dataset published between January 1, 2009, and December 30, 2023, to identify literature related to the application of artificial intelligence in chronic obstructive pulmonary disease (COPD). VOSviewer was utilized for visual analysis of countries, institutions, authors, co-cited authors, and keywords. CiteSpace was employed to analyze the intermediary centrality of institutions, references, keyword outbreaks, and co-cited literature. Relevant descriptive analysis tables were created using Excel2021 software. Results: This study included a total of 646 papers from WOS. The number of papers remained small and stable from 2009 to 2017 but started increasing significantly annually since 2018. The United States had the highest number of publications among countries/regions while Silverman Edwin K and Harvard Medical School were the most prolific authors and institutions respectively. Lynch DA, Kirby M. and Vestbo J. were among the top three most cited authors overall. Scientific Reports had the largest number of publications while Radiology ranked as one of the top ten influential journals. The Genetic Epidemiology of COPD (COPDGene) Study Design was frequently cited. Through keyword clustering analysis, all keywords were categorized into four groups: epidemiological study of COPD; AI-assisted imaging diagnosis; AI-assisted diagnosis; and AI-assisted treatment and prognosis prediction in the COPD research field. Currently, hot research topics include explainable artificial intelligence framework, chest CT imaging, and lung radiomics. Conclusion: At present, AI is predominantly employed in genetic biology, early diagnosis, risk staging, efficacy evaluation, and prediction modeling of COPD. This study's results offer novel insights and directions for future research endeavors related to COPD.

CTCF mediates CD8+ effector differentiation through dynamic redistribution and genomic reorganization.

Differentiation of effector CD8+ T cells is instructed by stably and dynamically expressed transcription regulators. Here we show that naive-to-effector differentiation was accompanied by dynamic CTCF redistribution and extensive chromatin architectural changes. Upon CD8+ T cell activation, CTCF acquired de novo binding sites and anchored novel chromatin interactions, and these changes were associated with increased chromatin accessibility and elevated expression of cytotoxic program genes including Tbx21, Ifng, and Klrg1. CTCF was also evicted from its ex-binding sites in naive state, with concomitantly reduced chromatin interactions in effector cells, as observed at memory precursor-associated genes including Il7r, Sell, and Tcf7. Genetic ablation of CTCF indeed diminished cytotoxic gene expression, but paradoxically elevated expression of memory precursor genes. Comparative Hi-C analysis revealed that key memory precursor genes were harbored within insulated neighborhoods demarcated by constitutive CTCF binding, and their induction was likely due to disrupted CTCF-dependent insulation. CTCF thus promotes cytotoxic effector differentiation by integrating local chromatin accessibility control and higher-order genomic reorganization.