{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:11:50Z","timestamp":1789049510395,"version":"build-2803163510"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The incidence of obesity, a condition characterized by systemic chronic inflammation, has reached pandemic proportions and is a poor prognostic factor in many pathologic states. However, its role on immune parameters has been diverse and at times contradictory. We have previously demonstrated that obesity can result in what has been called the \u201cobesity paradox\u201d which results in increased T cell exhaustion, but also greater efficacy of immune checkpoint blockade in cancer treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The role of obesity, particularly in the context of aging, has not been robustly explored using preclinical models. We therefore evaluated how age impacts the immune environment on T cell development and function using diet-induced obese (DIO) mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that DIO mice initially displayed greater thymopoiesis but then developed greater thymic involution over time compared to their lean counterparts. Both aging and obesity resulted in increased T cell memory conversion combined with increased expression of T cell exhaustion markers and Treg expansion. This increased T cell immunosuppression with age then resulted in a loss of anti-tumor efficacy by immune checkpoint inhibitors (ICIs) in older DIO mice compared to the younger DIO counterparts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These results suggest that both aging and obesity contribute to T cell dysfunction resulting in increased thymic involution. This combined with increased T cell exhaustion and immunosuppressive parameters affects immunotherapy efficacy reducing the advantage of obesity in cancer immunotherapy responses.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1012016","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T14:19:52Z","timestamp":1674742792000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Aging augments obesity-induced thymic involution and peripheral T cell exhaustion altering the \u201cobesity paradox\u201d"],"prefix":"10.3389","volume":"13","author":[{"given":"Logan V.","family":"Vick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig P.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam T.","family":"Khuat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordelia","family":"Dunai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan G.","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Stoffel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Yendamuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Randall","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarbajit","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Barbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Canter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arta M.","family":"Monjazeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-42542-9_1","article-title":"Obesity and risk of cancer: An introductory overview","volume-title":"Obesity and cancer","author":"Pischon","year":"2016"},{"key":"B2","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1111\/j.1476-5381.2011.01472.x","article-title":"Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction","volume":"165","author":"Barton","year":"2012","journal-title":"Br J Pharmacol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005060638","article-title":"Obesity and risk for chronic renal failure","volume":"17","author":"Ejerblad","year":"2006","journal-title":"JASN"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.metabol.2018.09.005","article-title":"The epidemiology of obesity","volume":"92","author":"Chooi","year":"2019","journal-title":"Metabolism"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1017\/S0029665112000092","article-title":"Obesity, inflammation and the immune system","volume":"71","author":"de Heredia","year":"2012","journal-title":"Proc Nutr Soc"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25102","article-title":"Inflammation, stress, and diabetes","volume":"115","author":"Wellen","year":"2005","journal-title":"J Clin Invest"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1684\/ecn.2018.0415","article-title":"Obesity and inflammation","volume":"29","author":"Karczewski","year":"2018","journal-title":"Eur Cytokine Netw"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.039","article-title":"Geroscience: Linking aging to chronic disease","volume":"159","author":"Kennedy","year":"2014","journal-title":"Cell"},{"key":"B10","article-title":"Immune system, cell senescence, aging and longevity - inflamm-aging reappraised","volume":"19","author":"Salvioli","year":"2013","journal-title":"Current Pharmaceutical Design"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/08820139.2018.1552392","article-title":"Inflammaging","volume":"47","author":"Kirkwood","year":"2018","journal-title":"Immunol Investigations"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1515\/hmbci-2018-0083\/html","article-title":"Obesity-induced immune dysfunction and immunosuppression: TEM observation of visceral and subcutaneous lymph node microarchitecture and immune cell interactions","volume":"39","author":"Solt","year":"2019","journal-title":"Hormone Mol Biol Clin Invest"},{"key":"B13","first-page":"21","article-title":"Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages","volume":"3","author":"Okwan-Duodu","year":"2013","journal-title":"Am J Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000021","article-title":"Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: Implications for systemic inflammation and insulin resistance","volume":"185","author":"Yang","year":"2010","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2010.10.012","article-title":"Obesity activates toll-like receptor-mediated proinflammatory signaling cascades in the adipose tissue of mice","volume":"23","author":"Kim","year":"2012","journal-title":"J Nutr Biochem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-030803","article-title":"Leptin and the proinflammatory state associated with human obesity","volume":"89","author":"Hukshorn","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B17","article-title":"Hematopoiesis with obesity and exercise: Role of the bone marrow niche","volume":"23","author":"Emmons","year":"2017","journal-title":"Exercise Immunology Review"},{"key":"B18","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.stem.2017.02.009","article-title":"Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration","volume":"20","author":"Ambrosi","year":"2017","journal-title":"Cell Stem Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170690","article-title":"Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression","volume":"215","author":"Lee","year":"2017","journal-title":"J Exp Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-018-0424-1","article-title":"Marrow adiposity and hematopoiesis in aging and obesity: Exercise as an intervention","volume":"16","author":"Patel","year":"2018","journal-title":"Curr Osteoporos Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205129109","article-title":"Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice","volume":"109","author":"Trottier","year":"","journal-title":"PNAS"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-213595","article-title":"Obesity accelerates thymic aging","volume":"114","author":"Yang","year":"2009","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2011.208","article-title":"Obesity is associated with impaired immune response to influenza vaccination in humans","volume":"36","author":"Sheridan","year":"2012","journal-title":"Int J Obes"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903220","article-title":"Diet-induced obesity impairs the T cell memory response to influenza virus infection","volume":"184","author":"Karlsson","year":"2010","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/137.5.1236","article-title":"Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus","volume":"137","author":"Smith","year":"2007","journal-title":"J Nutr"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0221-5","article-title":"Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade","volume":"25","author":"Wang","year":"2019","journal-title":"Nat Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.9.2860.009k35_2860_2868","article-title":"Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging","volume":"95","author":"Fagnoni","year":"2000","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2014.01.003","article-title":"Naive T cells: The crux of cellular immune aging","volume":"54","author":"Appay","year":"2014","journal-title":"Experimental Gerontology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00316","article-title":"The effect of age on thymic function","volume":"4","author":"Palmer","year":"2013","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714478115","article-title":"Thymic involution and rising disease incidence with age","volume":"115","author":"Palmer","year":"2018","journal-title":"Proc Natl Acad Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.752484","article-title":"Mechanisms by which obesity promotes acute graft-Versus-Host disease in mice","volume":"12","author":"Khuat","year":"2021","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100587","article-title":"Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth","volume":"189","author":"James","year":"2012","journal-title":"J Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6762","article-title":"Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob\/ob mice","volume":"104","author":"Howard","year":"1999","journal-title":"J Clin Invest"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.1.169","article-title":"Leptin selectively augments thymopoiesis in leptin deficiency and lipopolysaccharide-induced thymic atrophy","volume":"177","author":"Hick","year":"2006","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"12284","DOI":"10.1038\/s41598-019-48678-0","article-title":"Linkage of CD8+ T cell exhaustion with high-fat diet-induced tumourigenesis","volume":"9","author":"Kado","year":"2019","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining \u2018T cell exhaustion.\u2019","volume":"19","author":"Blank","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/path.5435","article-title":"T-Cell exhaustion interrelates with immune cytolytic activity to shape the inflamed tumor microenvironment","volume":"251","author":"Cai","year":"2020","journal-title":"J Pathology."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e139793","DOI":"10.1172\/jci.insight.139793","article-title":"Obesity results in adipose tissue T cell exhaustion","volume":"6","author":"Porsche","year":"2021","journal-title":"JCI Insight"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0506364","article-title":"Changes of CD4+CD25+Foxp3+ regulatory T cells in aged balb\/c mice","volume":"81","author":"Zhao","year":"2007","journal-title":"J Leukocyte Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1159\/000355303","article-title":"Regulatory T cells and the immune aging process: A mini-review","volume":"60","author":"Jagger","year":"2014","journal-title":"GER"},{"key":"B42","unstructured":"Age-related tumor growth in mice is related to integrin \u03b1 4 in CD8+ T cells"},{"key":"B43","unstructured":"Obesity has a systemic effect on immune cells in na\u00efve and cancer-bearing mice"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0126686","article-title":"Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells","volume":"10","author":"Mendonsa","year":"2015","journal-title":"PloS One"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1172\/JCI151347","article-title":"Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma","volume":"131","author":"Chakraborty","year":"2021","journal-title":"J Clin Invest"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(76)90109-8","article-title":"The development of obesity, hyperinsulinemia, and hyperglycemia in ob\/ob mice","volume":"25","author":"Dubuc","year":"1976","journal-title":"Metabolism"},{"key":"B47","article-title":"Development and consequences of insulin resistance: lessons from animals with hyperinsulinaemia","volume":"22","author":"Shafrir","year":"1996","journal-title":"Diabetes Metab"},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1002\/0471142301.ns0938s59","article-title":"Diet-induced models of obesity (DIO) in rodents","volume":"59","author":"Bagnol","year":"2012","journal-title":"Current Protocols in Neuroscience"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116621","article-title":"Insulin-like growth factor-1 stimulation of lymphopoiesis","volume":"92","author":"Clark","year":"1993","journal-title":"J Clin Invest"},{"key":"B50","doi-asserted-by":"crossref","DOI":"10.1210\/edrv.18.2.0296","article-title":"The somatogenic hormones and insulin-like growth factor-1: Stimulators of lymphopoiesis and immune function","volume":"18","author":"Clark","year":"1997","journal-title":"Endocrine Reviews"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210042","article-title":"Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function","volume":"219","author":"Dyck","year":"2022","journal-title":"J Exp Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T Cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20142237","article-title":"Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells","volume":"212","author":"Odorizzi","year":"2015","journal-title":"J Exp Med"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.03.030","article-title":"Obesity expands a distinct population of T cells in adipose tissue and increases vulnerability to infection","volume":"27","author":"Misumi","year":"2019","journal-title":"Cell Rep"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201706-447AW","article-title":"Obesity impairs the adaptive immune response to influenza virus","volume":"14","author":"Green","year":"","journal-title":"Ann Am Thorac Soc"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2103730118","article-title":"Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice","volume":"118","author":"Nakajima","year":"2021","journal-title":"Proc Natl Acad Sci"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.62420","article-title":"The effects of age and systemic metabolism on anti-tumor T cell responses","volume":"9","author":"Drijvers","year":"2020","journal-title":"eLife"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1012016\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T14:20:01Z","timestamp":1674742801000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1012016\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,26]]},"references-count":57,"alternative-id":["10.3389\/fimmu.2022.1012016"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1012016","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,26]]},"article-number":"1012016"}}