Article
Multidisciplinary Sciences
Muhammad Munir Iqbal, Michael Serralha, Parwinder Kaur, David Martino
Summary: T-cell activation induces specific gene expression programs that regulate energy generation, biosynthesis, cell cycle progression, and cell differentiation. This study used omni ATAC-seq method to characterize chromatin changes induced by T-cell activation. The research identified thousands of chromatin accessibility peaks associated with T-cell activation, with significant changes in gene expression related to cell cycle regulation, metabolism, and inflammatory response pathways.
SCIENTIFIC REPORTS
(2021)
Article
Multidisciplinary Sciences
Fabienne Mazerolles, Frederic Rieux-Laucat
Summary: The expression of co-signalling receptors on T cells plays a crucial role in regulating T cell responses, and an imbalance between activating and inhibitory signals may lead to autoimmunity. Research showed that activated TEFFs and TREGs express different co-signalling receptors, and the expression of PD-L1 on activated TEFFs is correlated with their proliferation.
Article
Medicine, Research & Experimental
Kensuke Suga, Akira Suto, Shigeru Tanaka, Yutaka Sugawara, Takahiro Kageyama, Junichi Ishikawa, Yoshie Sanayama, Kei Ikeda, Shunsuke Furuta, Shin-Ichiro Kagami, Arifumi Iwata, Koichi Hirose, Kotaro Suzuki, Osamu Ohara, Hiroshi Nakajima
Summary: Methotrexate (MTX) is a common treatment for rheumatoid arthritis (RA) but its precise mechanisms of action remain unclear. In this study, DNA microarray analyses of CD4+ T cells in RA patients revealed that TP63, specifically its isoform TAp63, was downregulated after MTX treatment. TAp63 was highly expressed in Th17 cells and suppressed by MTX in vitro. Knockdown of TAp63 in mouse Th17 cells improved arthritis symptoms. Furthermore, TAp63 knockdown in CD4+ T cells promoted Foxp3 expression and enhanced the suppressive function of induced Treg cells. In summary, TAp63 suppresses Foxp3 expression and worsens autoimmune arthritis.
Article
Multidisciplinary Sciences
Nozomu Takata, Jason M. Miska, Marc A. Morgan, Priyam Patel, Leah K. Billingham, Neha Joshi, Matthew J. Schipma, Zachary J. Dumar, Nikita R. Joshi, Alexander V. Misharin, Ryan B. Embry, Luciano Fiore, Peng Gao, Lauren P. Diebold, Gregory S. McElroy, Ali Shilatifard, Navdeep S. Chandel, Guillermo Oliver
Summary: Using eye organoids and mouse models, the authors demonstrate that lactate plays a bioenergetic independent role as a cell signaling molecule during early eye formation in mice. The study reveals the importance of aerobic glycolysis in retinal development and identifies specific glucose transporters and glycolytic genes involved. Lactate-mediated upregulation of eye-field transcription factors is controlled by epigenetic modifications.
NATURE COMMUNICATIONS
(2023)
Article
Pathology
Divya Sahu, Jianya Huan, Huawei Wang, Debashis Sahoo, Darren E. Casteel, Richard L. Klemke, Gerry R. Boss, Donna E. Hansel
Summary: Bladder cancer invasion is linked to mTORC2 activity, with increased iNOS expression identified as a key factor in invasion.
AMERICAN JOURNAL OF PATHOLOGY
(2021)
Editorial Material
Cell & Tissue Engineering
Pierre A. Coulombe, Sara A. Wickstrom
Summary: The study demonstrates that contractility in suprabasally located keratinocytes non-cell-autonomously regulates the replication and differentiation of stem/progenitor keratinocytes in the basal layer of epidermis, expanding our understanding of the niche that regulates stem/progenitor cells in skin.
Article
Medicine, Research & Experimental
Shuna Liu, Ziqi Tao, Jianfang Lou, Rong Li, Xin Fu, Juan Xu, Ting Wang, Lei Zhang, Wenwen Shang, Yepeng Mao, Fang Wang
Summary: This study reveals the important role of CD4(+)CCR8(+) Tregs in the immune microenvironment of ovarian cancer, and CCR8 and its ligands CCL1 and CCL18 play a key regulatory role in the migration and infiltration of CD4(+) T cells.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Biology
George Elias, Pieter Meysman, Esther Bartholomeus, Nicolas De Neuter, Nina Keersmaekers, Arvid Suls, Hilde Jansens, Aisha Souquette, Hans De Reu, Marie-Paule Emonds, Evelien Smits, Eva Lion, Paul G. Thomas, Geert Mortier, Pierre Van Damme, Philippe Beutels, Kris Laukens, Viggo Van Tendeloo, Benson Ogunjimi
Summary: This study demonstrates the significant impact of preexisting memory CD4 T cell clones on vaccine-induced immunity to hepatitis B. The presence of these clones can predict the strength and timing of the immune response to vaccination.
Review
Cell Biology
David A. Lewis, Tony Ly
Summary: CD8(+) T cells are crucial in immunity and immuno-oncology, as they undergo complex cellular growth, cell cycle entry, and differentiation to produce antigen-specific cytotoxic T lymphocytes. Some activated T cells will differentiate into memory T cells which are essential in adaptive immunity. This review explores the control of cell cycle entry in CD8(+) T cells and the interaction between these mechanisms and pathways regulating immunological phenotypes.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Immunology
Bilade Cherqaoui, Frederic Cremazy, Marc Lauraine, Ghazal Shammas, Roula Said-Nahal, Hendrick Mambu Mambueni, Felicie Costantino, Marine Fourmont, Audrey Hulot, Henri-Jean Garchon, Simon Glatigny, Luiza M. Araujo, Maxime Breban
Summary: The naïve CD4+ T cells of B27-rats exhibit a predisposition towards Th17 differentiation due to a STAT1 deficiency, which occurs early and is associated with an epigenetic Th17 bias. This molecular phenomenon may contribute to the persistent proinflammatory skew of CD4+ T cells in SpA patients, providing new insights for understanding and treating SpA.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Immunology
Casimiro Luca Gigliotti, Elena Boggio, Francesco Favero, Danny Incarnato, Claudio Santoro, Salvatore Oliviero, Jose Maria Rojo, Silvia Zucchelli, Francesca Persichetti, Gianluca Baldanzi, Umberto Dianzani, Davide Cora
Summary: ICOS and CD28 costimulatory signals play distinct roles in the activation of naive T cells by modulating different sets of immunological and immunometabolic genes.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Hematology
Dalia E. Gaddis, Lindsey E. Padgett, Runpei Wu, Anh Nguyen, Chantel McSkimming, Huy Q. Dinh, Daniel J. Araujo, Angela M. Taylor, Coleen A. McNamara, Catherine C. Hedrick
Summary: The study found dysregulated expression of metabolism genes in CD4 T cells from atherosclerotic mice, and impaired glucose uptake, proliferation, and activation in these cells. Furthermore, a reduction in naive CD4 T cells and their proliferative capacity was observed in subjects with high cardiovascular disease, highlighting the dysfunction in CD4 T-cell metabolism and immune responses during atherosclerosis. Targeting metabolic pathways within naive CD4 T cells could offer novel therapeutic approaches for improving CD4 T-cell responses against atheroprogression.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Christina Kiel, Tobias Strunz, Daniele Hasler, Gunter Meister, Felix Grassmann, Bernhard H. F. Weber
Summary: This study aimed to identify allele-specific target genes of hsa-miR-4513. A total of 23 allele-specific hsa-miR-4513 target genes were identified and their regulation was confirmed through experimental validation. These genes are linked to several phenotypes previously reported to be associated with hsa-miR-4513, providing promising candidates for functional pathobiological research on hsa-miR-4513 and its seed polymorphism rs2168518.
HUMAN MOLECULAR GENETICS
(2022)
Article
Chemistry, Multidisciplinary
Dacheng Ma, Qichen Yuan, Fei Peng, Victor Paredes, Hongzhi Zeng, Emmanuel C. Osikpa, Qiaochu Yang, Advaith Peddi, Anika Patel, Megan S. Liu, Zheng Sun, Xue Gao
Summary: This study developed a scalable chemically inducible dimerization platform (PROTAC-CID) based on proteolysis-targeting chimera, which enables inducible gene regulation and gene editing. It can fine-tune gene expression at gradient levels or multiplex biological signals. By coupling it with genetic circuits, digitally inducible expression of DNA recombinases and base-and prime-editors for transient genome manipulation are achieved. Furthermore, a compact PROTAC-CID system is packaged into adeno-associated viral vectors for inducible and reversible gene activation in vivo. This work provides a versatile molecular toolbox for chemically inducible gene regulation in human cells and mice.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Immunology
Ming Zhao, Sujie Jia, Xiaofei Gao, Hong Qiu, Ruifang Wu, Haijing Wu, Qianjin Lu
Summary: This study revealed 802 upregulated and 598 downregulated proteins in iTfh cells compared to naive CD4(+) T cells. Intensive bioinformatics analysis provided insights into the biological processes, cellular compartments, molecular functions, KEGG pathways, and protein-protein interactions of these differentially expressed proteins. The acetylome data showed differential levels of lysine acetylation in iTfh cells, with a specific focus on core histones, suggesting a role for protein acetylation and epigenetic mechanisms in regulating Tfh cell differentiation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Caleb R. Glassman, Yamuna Kalyani Mathiharan, Kevin M. Jude, Leon Su, Ouliana Panova, Patrick J. Lupardus, Jamie B. Spangler, Lauren K. Ely, Christoph Thomas, Georgios Skiniotis, K. Christopher Garcia
Summary: The structural mechanism of receptor sharing used by IL-12 family cytokines can be utilized to tune the cytokine axis for therapeutics, as demonstrated by the design of IL-12 partial agonists that elicited anti-tumor immunity in vivo.
Article
Immunology
Robert A. Saxton, Lukas T. Henneberg, Marco Calafiore, Leon Su, Kevin M. Jude, Alan M. Hanash, K. Christopher Garcia
Summary: This study engineered a high-affinity IL-22 superagonist to investigate the molecular mechanisms of the IL-22 signaling pathway. They found that precise control of IL-22 signaling can be achieved by modulating receptor expression levels and signaling bias, leading to tissue protection effects.
Article
Medicine, Research & Experimental
Toshihito Hirai, Teresa L. Ramos, Po-Yu Lin, Federico Simonetta, Leon L. Su, Lora K. Picton, Jeanette Baker, Jian-Xin Lin, Peng Li, Kinya Seo, Juliane K. Lohmeyer, Sara B. Wagers, Melissa Mavers, Warren J. Leonard, Bruce R. Blazar, K. Christopher Garcia, Robert S. Negrin
Summary: The study demonstrates an innovative approach to enhance the expansion and target cell stimulation ability of Treg cells through engineered orthogonal IL-2/IL-2R pair, which improves the potential for organ transplantation tolerance.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Multidisciplinary Sciences
Robert A. Saxton, Naotaka Tsutsumi, Leon L. Su, Gita C. Abhiraman, Kritika Mohan, Lukas T. Henneberg, Nanda G. Aduri, Cornelius Gati, K. Christopher Garcia
Summary: By determining the structure of the IL-10 receptor complex and uncovering differences in IL-10 response thresholds across immune cell populations, this study provides a mechanistic blueprint for manipulating the pleiotropic actions of IL-10. Some IL-10 variants displayed myeloid-biased activity, suppressing macrophage activation without stimulating inflammatory CD8(+) T cells, thus uncoupling the major opposing functions of IL-10.
Article
Biology
Caleb R. Glassman, Leon Su, Sonia S. Majri-Morrison, Hauke Winkelmann, Fei Mo, Peng Li, Magdiel Perez-Cruz, Peggy P. Ho, Ievgen Koliesnik, Nadine Nagy, Tereza Hnizdilova, Lora K. Picton, Marek Kovar, Paul Bollyky, Lawrence Steinman, Everett Meyer, Jacob Piehler, Warren J. Leonard, K. Christopher Garcia
Summary: Interleukin-2 (IL-2) is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions, with different sensitivities in immune cells due to cell type and activation state-dependent expression of receptors and signaling pathway components. Using structure-based design, IL-2 variants were created to titrate maximum signal strength across cell types, leading to cell type-dependent differences in gene expression. IL-2 partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions.
Article
Cell Biology
Qian Zhang, Morgan E. Hresko, Lora K. Picton, Leon Su, Michael J. Hollander, Selene Nunez-Cruz, Zheng Zhang, Charles-Antoine Assenmacher, Jonathan T. Sockolosky, K. Christopher Garcia, Michael C. Milone
Summary: Researchers have successfully created a pair of human orthogonal IL-2 and orthogonal IL-2 receptor through engineering, which can deliver IL-2 signal without toxicity, and demonstrated that this approach can enhance the antitumor efficacy of engineered T cells.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Gastroenterology & Hepatology
Adam Blaisdell, Yan Zhou, Michael G. Kattah, Susan J. Fisher, Uma Mahadevan
Summary: This study revealed a previously unrecognized role for alpha(4)beta(7) and MAdCAM-1 in human placental development. More clinical and histological data from Vedolizumab-treated pregnant patients will be necessary to determine whether this medication poses any risk to the mother and fetus.
INFLAMMATORY BOWEL DISEASES
(2022)
Article
Multidisciplinary Sciences
Junming Ren, Alexander E. Chu, Kevin M. Jude, Lora K. Picton, Aris J. Kare, Leon Su, Alejandra Montano Romero, Po-Ssu Huang, K. Christopher Garcia
Summary: Affinity maturation of protein-protein interactions is crucial in therapeutic protein development. Computational design can provide high-affinity IL-2 variants without interface engineering. Stabilizing the global IL-2 structure instead of receptor binding interfaces, we designed thermostable IL-2 variants with increased affinity for IL-2R beta, exhibiting IL-2 superkine-like activities.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Geil R. Merana, Laura R. Dwyer, Miqdad O. Dhariwala, Antonin Weckel, Jeanmarie R. Gonzalez, Joy N. Okoro, Jarish N. Cohen, Courtney M. Tamaki, Jungmin Han, Preston Tasoff, Yasmin Palacios-Calderon, Connie W. Y. Ha, Susan Lynch, Julia A. Segre, Heidi H. Kong, Michael G. Kattah, Averil Ma, Tiffany C. Scharschmidt
Summary: This study reveals that gut inflammation can disrupt the response of the skin to commensal bacteria, leading to an association between skin inflammation and intestinal diseases.
Article
Multidisciplinary Sciences
Anusha Kalbasi, Mikko Siurala, Leon L. Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V. Kremer, Amy L. Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C. Rommel, Enrico Radaelli, Regina M. Young, Warren J. Leonard, Antoni Ribas, Carl H. June, K. Christopher Garcia
Summary: Synthetic receptor signaling has the potential to enhance the functions of adoptively transferred T cells, improving their ability to treat solid tumors. By designing chimeric receptors with an orthogonal IL-2 receptor extracellular domain fused with the intracellular domain of receptors for common gamma-chain cytokines IL-4, IL-7, IL-9, and IL-21, T cells can be activated to elicit corresponding gamma(e) cytokine signals. This activation leads to improved anti-tumor efficacy in challenging mouse models of melanoma and pancreatic cancer.
Correction
Multidisciplinary Sciences
Anusha Kalbasi, Mikko Siurala, Leon L. Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V. Kremer, Amy L. Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C. Rommel, Enrico Radaelli, Regina M. Young, Warren J. Leonard, Antoni Ribas, Carl H. June, K. Christopher Garcia
Article
Biotechnology & Applied Microbiology
Xinbo Yang, Daisuke Nishimiya, Sara Lochte, Kevin M. Jude, Marta Borowska, Christina S. Savvides, Michael Dougan, Leon Su, Xiang Zhao, Jacob Piehler, K. Christopher Garcia
Summary: This article introduces a strategy for the rapid isolation of highly peptide-specific and "MHC-restricted" antibodies, by re-engineering preselected antibodies that engage peptide-MHC in a manner structurally similar to conventional αβ-TCRs. The authors created structure-based libraries focused on the peptide-interacting residues of TCRm antibody complementarity-determining region (CDR) loops, and rapidly generated MHC-restricted antibodies to both mouse and human tumor antigens. This approach has the potential to yield tumor antigen-specific antibodies in several weeks, enabling rapid clinical translation.
NATURE BIOTECHNOLOGY
(2023)
Article
Chemistry, Applied
Xiao-nan Yang, Ben Qin, Hong-mei Li, Jian-hua Miao, Sun-chul Kang
Summary: The essential oil extracted from Forsythia koreana flowers exhibited anti-inflammatory activity and could be potentially used in the development of anti-inflammatory products.
NATURAL PRODUCT RESEARCH
(2023)
Correction
Multidisciplinary Sciences
Anusha Kalbasi, Mikko Siurala, Leon L. Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V. Kremer, Amy L. Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C. Rommel, Enrico Radaelli, Regina M. Young, Warren J. Leonard, Antoni Ribas, Carl H. June, K. Christopher Garcia
Article
Medicine, Research & Experimental
Iulia Rusu, Elvira Mennillo, Jared L. Bain, Zhongmei Li, Xiaofei Sun, Kimberly M. Ly, Yenny Y. Rosli, Mohammad Naser, Zunqiu Wang, Rommel Advincula, Philip Achacoso, Ling Shao, Bahram Razani, Ophir D. Klein, Alexander Marson, Jessie A. Turnbaugh, Peter J. Turnbaugh, Barbara A. Malynn, Averil Ma, Michael G. Kattah
Summary: Anti-TNF therapy is effective for treating inflammatory bowel disease (IBD), but some patients don't respond well to this treatment. In this study, researchers found that the deletion of certain genes in intestinal epithelial cells (IECs) can sensitize mice to both TNF-dependent and TNF-independent cell death. The study also showed that microbial signals, MyD88, and LT alpha all contribute to the TNF-independent intestinal injury. These findings highlight the importance of TNF-independent pathways in the development of IBD and suggest potential targets for therapy.
JOURNAL OF CLINICAL INVESTIGATION
(2022)