Immunology
Abstract
Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation–mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.
Authors
Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou
Abstract
Tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) are emerging solid-tumor indicators of prognosis and response to immunotherapy. Considering that tumorigenesis requires metabolic reprogramming and subsequent TME remodeling, the discovery of TLS metabolic regulators is expected to produce immunotherapeutic targets. To identify such metabolic regulators, we constructed a metabolism-focused sgRNA library and performed an in vivo CRISPR screening in an orthotopic lung tumor mouse model. Combined with The Cancer Genome Atlas database analysis of TLS-related metabolic hub genes, we found that the loss of Acat1 in tumor cells sensitized tumors to anti-PD1 treatment, accompanied by increased TLS in the TME. Mechanistic studies revealed that ACAT1 resulted in mitochondrial protein hypersuccinylation in lung tumor cells and subsequently enhanced mitochondrial oxidative metabolism, which impeded TLS formation. Elimination of ROS by NAC or Acat1 knockdown promoted B cell aggregation and TLS construction. Consistently, data from tissue microassays of 305 patients with lung cancer showed that TLS were more abundant in non–small cell lung cancer (NSCLC) tissues with lower ACAT1 expression. Intratumoral ACAT1 expression was associated with poor immunotherapy outcomes in patients with NSCLC. In conclusion, our results identified ACAT1 as a metabolic regulator of TLS and a promising immunotherapeutic target in NSCLC.
Authors
Mengxia Jiao, Yifan Guo, Hongyu Zhang, Haoyu Wen, Peng Chen, Zhiqiang Wang, Baichao Yu, Kameina Zhuma, Yuchen Zhang, Jingbo Qie, Yun Xing, Pengyuan Zhao, Zihe Pan, Luman Wang, Dan Zhang, Fei Li, Yijiu Ren, Chang Chen, Yiwei Chu, Jie Gu, Ronghua Liu
Abstract
The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics remain unclear. Herein, we investigated the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+NK cell population within the liver metastasis (LM) environment of colorectal cancer (CRC). We show that CD49a+NK cells had the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promoted CD49a+NK cell accumulation and persistence in metastasis where NK cells co-localize with macrophages in CXCL9 and CXCL10 rich areas. By mining a published scRNA-seq dataset of a cohort of treatment-naïve CRC patients, we confirmed the accumulation of CXCR3+NK cells in metastatic samples. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages impaired CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in LM. Conversely, CXCR3neg NK cells maintained a CD49a- phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+NK cell accumulation was impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in CRC LM.
Authors
Eleonora Russo, Chiara D'Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A. J. Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini
Abstract
Background: Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually-acquired HIV, yet the immunological mechanisms underlying this association are not well understood. Methods: To investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, Kinga Study participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples. Results: High-parameter flow cytometry revealed an increased frequency of cervical conventional CD4+ T cells (Tconv) expressing CCR5. However, we found no difference in number of CD3+CD4+CCR5+ cells in the CX or VT of BV+ versus BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV have an increased frequency of dysfunctional CX and VT CD39+ Tconv and CX tissue-resident CD69+CD103+ Tconv, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations. Conclusion: Our comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV including increased HIV susceptibility.
Authors
Finn MacLean, Adino Tesfahun Tsegaye, Jessica B. Graham, Jessica L. Swarts, Sarah C. Vick, Nicole B. Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K. Schroeder, Ayumi Saito, Corinne Mar, Katherine K. Thomas, Matthias Mack, Michelle C. Sabo, Bhavna H. Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Jairam R. Lingappa, Jennifer M. Lund
Abstract
Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3b-STAT3 pathway. Moreover, TAM-derived LGMN activated the integrin aV-AKT-P65 signaling to drive GBM cell proliferation and survival. Targeting LGMN-directed macrophage (inhibiting GSK3b and STAT3) and GBM cell (inhibiting integrin aV) mechanisms resulted in an anti-tumor effect in immunocompetent GBM mouse models that was further enhanced when combined with anti-PD1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN in promoting GBM progression and immunosuppression, providing effective therapeutic targets for improving immunotherapy in GBM.
Authors
Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D. Lathia, Peiwen Chen
Maintenance of graft tissue-resident Foxp3+ cells is necessary for lung transplant tolerance in mice
Abstract
Mechanisms that mediate allograft tolerance differ between organs. We have previously shown that Foxp3+ T cell-enriched bronchus-associated lymphoid tissue (BALT) is induced in tolerant murine lung allografts and that these Foxp3+ cells suppress alloimmune responses locally and systemically. Here, we demonstrated that Foxp3+ cells that reside in tolerant lung allografts differed phenotypically and transcriptionally from those in the periphery and were clonally expanded. Using a mouse lung re-transplant model, we showed that recipient Foxp3+ cells were continuously recruited to the BALT within tolerant allografts. We identified distinguishing features of graft-resident and newly recruited Foxp3+ cells and showed that graft-infiltrating Foxp3+ cells acquired transcriptional profiles resembling those of graft-resident Foxp3+ cells over time. Allografts underwent combined antibody-mediated rejection (AMR) and acute cellular rejection (ACR) when recruitment of recipient Foxp3+ cells was prevented. Finally, we showed that local administration of IL-33 could expand and activate allograft-resident Foxp3+ cells providing a platform for the design of tolerogenic therapies for lung transplant recipients. Our findings establish graft-resident Foxp3+ cells as critical orchestrators of lung transplant tolerance and highlight the need to develop lung-specific immunosuppression.
Authors
Wenjun Li, Yuriko Terada, Yun Zhu Bai, Yuhei Yokoyama, Hailey M. Shepherd, Junedh M. Amrute, Amit I. Bery, Zhiyi Liu, Jason M. Gauthier, Marina Terekhova, Ankit Bharat, Jon H. Ritter, Varun Puri, Ramsey R. Hachem, Hēth R. Turnquist, Peter T. Sage, Alessandro Alessandrini, Maxim N. Artyomov, Kory J. Lavine, Ruben G. Nava, Alexander S. Krupnick, Andrew E. Gelman, Daniel Kreisel
Abstract
Tissue regenerative responses involve complex interactions between resident structural and immune cells. Recent reports indicate that accumulation of senescent cells during injury repair contributes to pathological tissue fibrosis. Using tissue-based spatial transcriptomics and proteomics, we identified upregulation of the immune checkpoint protein, cytotoxic T-lymphocyte associated protein 4 (CTLA4) on CD8+ T cells adjacent to regions of active fibrogenesis in human idiopathic pulmonary fibrosis (IPF) and in a murine model of repetitive bleomycin lung injury model of persistent fibrosis. In humanized CTLA4 knock-in mice, treatment with ipilimumab, an FDA-approved drug that targets CTLA4, resulted in accelerated lung epithelial regeneration and diminished fibrosis from repetitive bleomycin injury. Ipilimumab treatment resulted in the expansion of Cd3e+ T cells, diminished accumulation of senescent cells, and robust expansion of type 2 alveolar epithelial cells, facultative progenitor cells of the alveolar epithelium. Ex-vivo activation of isolated CTLA4-expressing CD8+ cells from mice with established fibrosis resulted in enhanced cytolysis of senescent cells, suggesting that impaired immune-mediated clearance of these cells contribute to persistence of lung fibrosis in this murine model. Our studies support the concept that endogenous immune surveillance of senescent cells may be essential in promoting tissue regenerative responses that facilitate the resolution of fibrosis.
Authors
Santosh Yadav, Muralidharan Anbalagan, Shamima Khatun, Devadharshini Prabhakaran, Justin Manges, Yasuka Matsunaga, James B. McLachlan, Joseph A. Lasky, Jay Kolls, Victor J. Thannickal
Abstract
CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.
Authors
Manuel A. Torres Acosta, Jonathan K. Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A. Helmin, Anthony M. Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E. Weinberg, Benjamin D. Singer
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset is crucial to establishing effective prevention strategies. Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) to characterize the immunophenotypes in blood from at-risk individuals (ARIs) identified through the presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared with patients with established RA and people in a healthy control group. We identified significant cell expansions in ARIs compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5lo naive B cell population was expanded in ACPA-positive FDRs. Further, we uncovered the molecular phenotype of the CCR2+CD4+ T cells, expressing high levels of Th17- and Th22-related signature transcripts including CCR6, IL23R, KLRB1, CD96, and IL22. Our integrated study provides a promising approach to identify targets to improve prevention strategy development for RA.
Authors
Jun Inamo, Joshua Keegan, Alec Griffith, Tusharkanti Ghosh, Alice Horisberger, Kaitlyn Howard, John F. Pulford, Ekaterina Murzin, Brandon Hancock, Salina T. Dominguez, Miranda G. Gurra, Siddarth Gurajala, Anna Helena Jonsson, Jennifer A. Seifert, Marie L. Feser, Jill M. Norris, Ye Cao, William Apruzzese, S. Louis Bridges, Vivian P. Bykerk, Susan Goodman, Laura T. Donlin, Gary S. Firestein, Joan M. Bathon, Laura B. Hughes, Andrew Filer, Costantino Pitzalis, Jennifer H. Anolik, Larry Moreland, Nir Hacohen, Joel M. Guthridge, Judith A. James, Carla M. Cuda, Harris Perlman, Michael B. Brenner, Soumya Raychaudhuri, Jeffrey A. Sparks, The Accelerating Medicines Partnership RA/SLE Network, V. Michael Holers, Kevin D. Deane, James Lederer, Deepak A. Rao, Fan Zhang
Abstract
BACKGROUND Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODS Using histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell–eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTS Asthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13–activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSION Together, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell–mucin-granulocyte cross-talk.FUNDING NIH grants HL080414, HL107202, and AI077439.
Authors
Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)