{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T02:51:33Z","timestamp":1787539893038,"version":"build-2736575974"},"reference-count":109,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["R01AG076373"],"award-info":[{"award-number":["R01AG076373"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Current models of microbiome, immune crosstalk center on extracellular receptor-mediated signaling, yet a critical observation challenges this paradigm: intracellular concentrations of gut-derived bacterial metabolites (GDBMs) in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells do not correlate with paired plasma levels, and it is intracellular, not circulating, GDBM burden that associates with metabolic pathway disruption and immune senescence. Here we propose the concept of an intracellular microbiome metabolome: a pool of aromatic GDBMs actively accumulated through carrier-mediated transport, retained through transcriptional suppression of efflux transporters, and integrated into host metabolic networks where metabolites directly engage intracellular senescence pathways. Using p-cresol sulfate (PCS) as a mechanistic prototype, we provide transcriptomic, proteomic, and metabolomic evidence implicating SLCO4A1\/OATP4A1 as the primary entry transporter, whose suppression following PCS exposure creates a feed-forward intracellular retention loop. Once accumulated, PCS functions as a direct agonist of the aryl hydrocarbon receptor (AhR), engaging five downstream effector programs, TGF-\u03b2\/SMAD signaling, Wnt\/\u03b2-catenin reprogramming, Foxp3-dependent Treg induction, Notch dysregulation, and PTGS2\/COX-2 induction with coordinate HPGD suppression driving PGE\n                    <jats:sub>2<\/jats:sub>\n                    excess via EP2\/EP4\/cAMP\/CREM, that converge on mTOR suppression, glycolytic collapse, and mitochondrial dysfunction. This metabolic collapse in turn activates the integrated stress response (ISR) as a downstream consequence, driving p16\/CDKN2A and p21\/CDKN1A induction and the full immunometabolic signature of accelerated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell aging. The plasma intracellular dissociation explains why circulating GDBM levels have failed to predict immune outcomes in HIV-1 infection, chronic kidney disease, and aging, and positions intracellular GDBM quantification as the biologically relevant exposure metric. We discuss three therapeutic intervention layers: reduction of microbial metabolite production, blockade of SLCO4A1-mediated entry and efflux suppression, and targeting the AhR signaling axis with downstream metabolic and ISR consequences.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1852583","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:26:21Z","timestamp":1785212781000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune cells harbor their own microbiome-derived metabolome: a new layer of immunometabolic regulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Lisa","family":"Daley-Bauer","sequence":"first","affiliation":[{"name":"Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Flantzer","sequence":"additional","affiliation":[{"name":"Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuya","family":"Kyu","sequence":"additional","affiliation":[{"name":"Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyce","family":"Godoy","sequence":"additional","affiliation":[{"name":"Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Emory University School of Medicine and Department of Global Health, Emory University Rollins School of Public Health","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent C.","family":"Marconi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Emory University School of Medicine and Department of Global Health, Emory University Rollins School of Public Health","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean P.","family":"Jones","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University School of Medicine","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souheil-Antoine","family":"Younes","sequence":"additional","affiliation":[{"name":"Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine","place":["Atlanta, GA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.041","article-title":"From dietary fiber to host physiology: Short-chain fatty acids as key bacterial metabolites","volume":"165","author":"Koh","year":"2016","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254766","article-title":"Small molecules from the human microbiota","volume":"349","author":"Donia","year":"2015","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature12726","article-title":"Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation","volume":"504","author":"Arpaia","year":"2013","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1241165","article-title":"The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis","volume":"341","author":"Smith","year":"2013","journal-title":"Science"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322269111","article-title":"The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition","volume":"111","author":"Chang","year":"2014","journal-title":"Proc Natl Acad Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5418.1362","article-title":"Identification of a nuclear receptor for bile acids","volume":"284","author":"Makishima","year":"1999","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/s41577-024-01057-x","article-title":"How bile acids and the microbiota interact to shape host immunity","volume":"24","author":"Lee","year":"2024","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.003","article-title":"Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22","volume":"39","author":"Zelante","year":"2013","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1038\/nm.4102","article-title":"CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands","volume":"22","author":"Lamas","year":"2016","journal-title":"Nat Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/toxins9020052","article-title":"p-cresyl sulfate","volume":"9","author":"Gryp","year":"2017","journal-title":"Toxins (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1172\/jci149571","article-title":"Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection","volume":"132","author":"Ferrari","year":"2022","journal-title":"J Clin Invest"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.204383","article-title":"Microbiome-derived metabolites shape CD4+ T-cell differentiation and immune aging in chronic HIV-1 infection","author":"Da Silva","year":"","journal-title":"JCI Insight"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0125-8","article-title":"The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease","volume":"19","author":"Rothhammer","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-1252-6","article-title":"The eIF2\u03b1 kinases: their structures and functions","volume":"70","author":"Donnelly","year":"2013","journal-title":"Cell Mol Life Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00354.x","article-title":"Characterization of uremic toxin transport by organic anion transporters in the kidney","volume":"65","author":"Deguchi","year":"2004","journal-title":"Kidney Int"},{"key":"B16","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1152\/physrev.00025.2013","article-title":"The organic anion transporter (OAT) family: A systems biology perspective","volume":"95","author":"Nigam","year":"2015","journal-title":"Physiol Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.03.013","article-title":"GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase","volume":"22","author":"Munn","year":"2005","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/jci31178","article-title":"Indoleamine 2,3-dioxygenase and tumor-induced tolerance","volume":"117","author":"Munn","year":"2007","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12040245","article-title":"Gut-derived metabolites and their role in immune dysfunction in chronic kidney disease","volume":"12","author":"Glorieux","year":"2020","journal-title":"Toxins (Basel)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12050300","article-title":"Chronic kidney disease-associated immune dysfunctions: Impact of protein-bound uremic retention solutes on immune cells","volume":"12","author":"Espi","year":"2020","journal-title":"Toxins (Basel)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2922","article-title":"Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family","volume":"273","author":"Tamai","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"B22","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1080\/00498250801986951","article-title":"Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family","volume":"38","author":"Hagenbuch","year":"2008","journal-title":"Xenobiotica"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1136\/gut.28.10.1221","article-title":"Short chain fatty acids in human large intestine, portal, hepatic and venous blood","volume":"28","author":"Cummings","year":"1987","journal-title":"Gut"},{"key":"B24","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1079\/pns2002207","article-title":"Regulation of short-chain fatty acid production","volume":"62","author":"Macfarlane","year":"2003","journal-title":"Proc Nutr Soc"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2001.02001.x","article-title":"p-Hydroxyphenylacetate decarboxylase from Clostridium difficile. A novel glycyl radical enzyme catalysing the formation of p-cresol","volume":"268","author":"Selmer","year":"2001","journal-title":"Eur J Biochem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s002489900020","article-title":"Formation of phenolic and indolic compounds by anaerobic bacteria in the human large intestine","volume":"33","author":"Smith","year":"1997","journal-title":"Microb Ecol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.115.064246","article-title":"Indole and tryptophan metabolism: Endogenous and dietary routes to Ah receptor activation","volume":"43","author":"Hubbard","year":"2015","journal-title":"Drug Metab Dispos"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812874106","article-title":"Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites","volume":"106","author":"Wikoff","year":"2009","journal-title":"Proc Natl Acad Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2021.115553","article-title":"Characterization of human sulfotransferases catalyzing the formation of p-cresol sulfate and identification of mefenamic acid as a potent metabolism inhibitor and potential therapeutic agent for detoxification","volume":"425","author":"Rong","year":"2021","journal-title":"Toxicol Appl Pharmacol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.2215\/cjn.00160116","article-title":"Metabolism, protein binding, and renal clearance of microbiota-derived p-cresol in patients with CKD","volume":"11","author":"Poesen","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.chom.2022.11.015","article-title":"Two distinct gut microbial pathways contribute to meta-organismal production of phenylacetylglutamine with links to cardiovascular disease","volume":"31","author":"Zhu","year":"2023","journal-title":"Cell Host Microbe"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.016","article-title":"A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors","volume":"180","author":"Nemet","year":"2020","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/bf03190428","article-title":"Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate","volume":"27","author":"Banoglu","year":"2002","journal-title":"Eur J Drug Metab Pharmacokinet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2215\/cjn.02940509","article-title":"p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients","volume":"4","author":"Meijers","year":"2009","journal-title":"Clin J Am Soc Nephrol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/mp.a001490.01","article-title":"The monocarboxylate transporter family\u2014Structure and functional characterization","volume":"64","author":"Halestrap","year":"2012","journal-title":"IUBMB Life"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2012.05.003","article-title":"The SLC16 gene family \u2013 Structure, role and regulation in health and disease","volume":"34","author":"Halestrap","year":"2013","journal-title":"Mol Aspects Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1097\/coh.0000000000000234","article-title":"Microbial translocation and microbiome dysbiosis in HIV-associated immune activation","volume":"11","author":"Zevin","year":"2016","journal-title":"Curr Opin HIV AIDS"},{"key":"B39","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1093\/infdis\/jiu409","article-title":"Intestinal microbiota, microbial translocation, and systemic inflammation in chronic HIV infection","volume":"211","author":"Dinh","year":"2015","journal-title":"J Infect Dis"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2013.116","article-title":"An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia","volume":"7","author":"Dillon","year":"2014","journal-title":"Mucosal Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"193ra91","DOI":"10.1126\/scitranslmed.3006438","article-title":"Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism","volume":"5","author":"Vujkovic-Cvijin","year":"2013","journal-title":"Sci Transl Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-025-01527-9","article-title":"Targeting immunosenescence and inflammaging: advancing longevity research","volume":"57","author":"Nguyen","year":"2025","journal-title":"Exp Mol Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00348-0","article-title":"Gut microbiome pattern reflects healthy ageing and predicts survival in humans","volume":"3","author":"Wilmanski","year":"2021","journal-title":"Nat Metab"},{"key":"B44","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41564-018-0306-4","article-title":"Gut microbiome structure and metabolic activity in inflammatory bowel disease","volume":"4","author":"Franzosa","year":"2019","journal-title":"Nat Microbiol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1237-9","article-title":"Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases","volume":"569","author":"Lloyd-Price","year":"2019","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","first-page":"3294","DOI":"10.1038\/s41467-018-05470-4","article-title":"Microbial tryptophan catabolites in health and disease","volume":"9","author":"Roager","year":"2018","journal-title":"Nat Commun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2848","article-title":"Microbial translocation in HIV infection: causes, consequences and treatment opportunities","volume":"10","author":"Sandler","year":"2012","journal-title":"Nat Rev Microbiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-3-s1-s98","article-title":"Microbial translocation is a cause of systemic immune activation in chronic HIV infection","volume":"12","author":"Brenchley","year":"2006","journal-title":"Nat Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.023","article-title":"Translocated microbiome composition determines immunological outcome in treated HIV infection","volume":"184","author":"Nganou-Makamdop","year":"2021","journal-title":"Cell"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/path.2276","article-title":"Immune activation and inflammation in HIV-1 infection: causes and consequences","volume":"214","author":"Appay","year":"2008","journal-title":"J Pathol"},{"key":"B51","article-title":"HIV disease progression: immune activation, microbes, and a leaky gut","volume":"15","author":"Douek","year":"2007","journal-title":"Top HIV Med"},{"key":"B52","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1053\/j.ajkd.2009.04.022","article-title":"The uremic retention solute p-cresyl sulfate and markers of endothelial damage","volume":"54","author":"Meijers","year":"2009","journal-title":"Am J Kidney Dis"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.2215\/cjn.00300113","article-title":"Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD","volume":"8","author":"Poesen","year":"2013","journal-title":"Clin J Am Soc Nephrol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1007\/s10157-013-0902-9","article-title":"Human organic anion transporters function as a high-capacity transporter for p-cresyl sulfate, a uremic toxin","volume":"18","author":"Watanabe","year":"2014","journal-title":"Clin Exp Nephrol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1080\/00498250600861751","article-title":"Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition","volume":"36","author":"Bleasby","year":"2006","journal-title":"Xenobiotica"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242015187","article-title":"SLC22A11 inserts the uremic toxins indoxyl sulfate and P-cresol sulfate into the plasma membrane","volume":"24","author":"Tust","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242015419","article-title":"Renal organic anion transporters 1 and 3 in vitro: gone but not forgotten","volume":"24","author":"Caetano-Pinto","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00103","article-title":"Estrone sulfate transport and steroid sulfatase activity in colorectal cancer: implications for hormone replacement therapy","volume":"8","author":"Gilligan","year":"2017","journal-title":"Front Pharmacol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2008.00745.x","article-title":"Differential expression of influx and efflux transport proteins in human antigen presenting cells","volume":"17","author":"Skazik","year":"2008","journal-title":"Exp Dermatol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.946348","article-title":"SLCO4A1 expression is associated with activated inflammatory pathways in high-grade serous ovarian cancer","volume":"13","author":"Koller","year":"2022","journal-title":"Front Pharmacol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.cmet.2019.10.004","article-title":"Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring","volume":"30","author":"Pucino","year":"2019","journal-title":"Cell Metab"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002202","article-title":"Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions","volume":"13","author":"Haas","year":"2015","journal-title":"PLoS Biol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00053","article-title":"Role of SLC7A5 in metabolic reprogramming of human monocyte\/macrophage immune responses","volume":"9","author":"Yoon","year":"2018","journal-title":"Front Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0109-y","article-title":"The apical conjugate efflux pump ABCC2 (MRP2)","volume":"453","author":"Nies","year":"2007","journal-title":"Pflugers Arch"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120159197","article-title":"Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs","volume":"97","author":"Wijnholds","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.056564","article-title":"Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis","volume":"76","author":"Ahn","year":"2009","journal-title":"Mol Pharmacol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0111-1","article-title":"Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling","volume":"15","author":"Nigam","year":"2019","journal-title":"Nat Rev Nephrol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2634","article-title":"A biological basis for pharmacokinetics: the remote sensing and signaling theory","volume":"112","author":"Nigam","year":"2022","journal-title":"Clin Pharmacol Ther"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-030322-084058","article-title":"OAT, OATP, and MRP drug transporters and the remote sensing and signaling theory","volume":"63","author":"Nigam","year":"2023","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.12.4579","article-title":"Juxtaposition of domains homologous to protein kinases and histidyl-tRNA synthetases in GCN2 protein suggests a mechanism for coupling GCN4 expression to amino acid availability","volume":"86","author":"Wek","year":"1989","journal-title":"Proc Natl Acad Sci USA"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/s1097-2765(00)00028-9","article-title":"Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain","volume":"6","author":"Dong","year":"2000","journal-title":"Mol Cell"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-15-3376","article-title":"Genetic disruption of the multifunctional CD98\/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth","volume":"76","author":"Cormerais","year":"2016","journal-title":"Cancer Res"},{"key":"B73","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/bj20121098","article-title":"Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR","volume":"449","author":"Gallinetti","year":"2013","journal-title":"Biochem J"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300923","article-title":"LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells","volume":"191","author":"Hayashi","year":"2013","journal-title":"J Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/s1097-2765(03)00105-9","article-title":"An integrated stress response regulates amino acid metabolism and resistance to oxidative stress","volume":"11","author":"Harding","year":"2003","journal-title":"Mol Cell"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.81","article-title":"The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation","volume":"29","author":"Ye","year":"2010","journal-title":"EMBO J"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abg0791","article-title":"Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals","volume":"6","author":"Jin","year":"2021","journal-title":"Sci Immunol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.immuni.2014.04.007","article-title":"Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation","volume":"40","author":"Nakaya","year":"2014","journal-title":"Immunity"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.11.044","article-title":"Bidirectional transport of amino acids regulates mTOR and autophagy","volume":"136","author":"Nicklin","year":"2009","journal-title":"Cell"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.27.1_supplement.832.1","article-title":"A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1","volume":"340","author":"Bar-Peled","year":"2013","journal-title":"Science"},{"key":"B81","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.immuni.2017.12.012","article-title":"Regulation of the immune response by the aryl hydrocarbon receptor","volume":"48","author":"Gutierrez-Vazquez","year":"2018","journal-title":"Immunity"},{"key":"B82","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/nature06880","article-title":"Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor","volume":"453","author":"Quintana","year":"2008","journal-title":"Nature"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120245","article-title":"The aryl hydrocarbon receptor: multitasking in the immune system","volume":"32","author":"Stockinger","year":"2014","journal-title":"Annu Rev Immunol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01561","article-title":"The aryl hydrocarbon receptor (AhR) in the aging process: another puzzling role for this highly conserved transcription factor","volume":"10","author":"Brinkmann","year":"2019","journal-title":"Front Physiol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s00018-022-04520-x","article-title":"Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process","volume":"79","author":"Salminen","year":"2022","journal-title":"Cell Mol Life Sci"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2022.110445","article-title":"Mutual antagonism between aryl hydrocarbon receptor and hypoxia-inducible factor-1\u03b1 (AhR\/HIF-1\u03b1) signaling: Impact on the aging process","volume":"99","author":"Salminen","year":"2022","journal-title":"Cell Signalling"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.5551\/jat.34462","article-title":"Crucial role of the aryl hydrocarbon receptor (AhR) in indoxyl sulfate-induced vascular inflammation","volume":"23","author":"Ito","year":"2016","journal-title":"J Atheroscler Thromb"},{"key":"B88","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s11658-024-00550-4","article-title":"Uremic toxins mediate kidney diseases: the role of aryl hydrocarbon receptor","volume":"29","author":"Xie","year":"2024","journal-title":"Cell Mol Biol Lett"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-025-01172-x","article-title":"The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation","volume":"24","author":"Polonio","year":"2025","journal-title":"Nat Rev Drug Discov"},{"key":"B90","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3945\/jn.108.099259","article-title":"Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3'-diindolylmethane in breast cancer cells","volume":"139","author":"Degner","year":"2009","journal-title":"J Nutr"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.108176","article-title":"Recent advances in studies of 15-PGDH as a key enzyme for the degradation of prostaglandins","volume":"101","author":"Sun","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00222","article-title":"Molecular Mechanisms for cAMP-Mediated Immunoregulation in T cells - Role of Anchored Protein Kinase A Signaling Units","volume":"7","author":"Wehbi","year":"2016","journal-title":"Front Immunol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/j.immuni.2023.05.011","article-title":"Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses","volume":"56","author":"Bayerl","year":"2023","journal-title":"Immunity"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2013.02.001","article-title":"cAMP responsive element modulator: a critical regulator of cytokine production","volume":"19","author":"Rauen","year":"2013","journal-title":"Trends Mol Med"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01979-21","article-title":"Differential expression of CREM\/ICER isoforms is associated with the spontaneous control of HIV infection","volume":"13","author":"Luo","year":"2022","journal-title":"mBio"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s44318-025-00601-2","article-title":"Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues","volume":"44","author":"Saul","year":"","journal-title":"EMBO J"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-022-00601-z","article-title":"Cellular senescence: the good, the bad and the unknown","volume":"18","author":"Huang","year":"2022","journal-title":"Nat Rev Nephrol"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1172\/jci120245","article-title":"Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction","volume":"128","author":"Younes","year":"2018","journal-title":"J Clin Invest"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir507","article-title":"Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells","volume":"204","author":"Lederman","year":"2011","journal-title":"J Infect Dis"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.658420","article-title":"Mitochondrial functions are compromised in CD4 T cells from ART-controlled PLHIV","volume":"12","author":"Zhao","year":"2021","journal-title":"Front Immunol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-042909-093756","article-title":"HIV infection, inflammation, immunosenescence, and aging","volume":"62","author":"Deeks","year":"2011","journal-title":"Annu Rev Med"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0166759","article-title":"p16INK4a expression and immunologic aging in chronic HIV infection","volume":"11","author":"Ribeiro","year":"2016","journal-title":"PLoS One"},{"key":"B103","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.cell.2016.05.035","article-title":"Mitochondrial dynamics controls T cell fate through metabolic programming","volume":"166","author":"Buck","year":"2016","journal-title":"Cell"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1159\/000362502","article-title":"Mitochondrial metabolism in T cell activation and senescence: a mini-review","volume":"61","author":"Ron-Harel","year":"2015","journal-title":"Gerontology"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.20900\/immunometab20220013","article-title":"Mitochondrial exhaustion of memory CD4 T-cells in treated HIV-1 infection","volume":"4","author":"Younes","year":"2022","journal-title":"Immunometabolism"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.06.004","article-title":"Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs","volume":"29","author":"Tomb\u00e1cz","year":"2021","journal-title":"Mol Ther"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-020-0669-6","article-title":"Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing","volume":"15","author":"Cheng","year":"2020","journal-title":"Nat Nanotechnol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060301","article-title":"Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor","volume":"6","author":"Copp\u00e9","year":"2008","journal-title":"PLoS Biol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Pakos-Zebrucka","year":"2016","journal-title":"EMBO Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1852583\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:26:23Z","timestamp":1785212783000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1852583\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":109,"alternative-id":["10.3389\/fimmu.2026.1852583"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1852583","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"article-number":"1852583"}}