{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T04:15:02Z","timestamp":1778732102431,"version":"3.51.4"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Direct mammalian target of rapamycin (Rapa) complex 1 inhibition by short-term low-dose Rapa treatment has recently been shown to improve CD8 T cell immunological memory. Whereas these studies focused on memory development, the impact of low-dose Rapa on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. In this study, we investigated the impact of acute Rapa treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naive cells and the reduced formation of short-lived effector cells. Therefore, more than one cell type required for a protective effector immune response is impaired by Rapa in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of Rapa treatment as means to improve immune memory.<\/jats:p>","DOI":"10.4049\/jimmunol.1400188","type":"journal-article","created":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T07:46:21Z","timestamp":1402386381000},"page":"757-763","source":"Crossref","is-referenced-by-count":29,"title":["Immune Memory\u2013Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections"],"prefix":"10.1093","volume":"193","author":[{"given":"Emily L","family":"Goldberg","sequence":"first","affiliation":[{"name":"Department of Immunobiology, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona , Tucson, AZ 85721"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan J","family":"Smithey","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia K","family":"Lutes","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Department of Molecular and Cellular Biology, College of Science, University of Arizona , Tucson, AZ 85721"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L","family":"Uhrlaub","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janko","family":"Nikolich-\u017dugich","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Arizona Center on Aging, University of Arizona College of Medicine , Tucson, AZ 85724"},{"name":"Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona , Tucson, AZ 85721"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,7,15]]},"reference":[{"key":"2025030707230113200_r1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrm3025","article-title":"mTOR: from growth signal integration to cancer, diabetes and ageing","volume":"12","author":"Zoncu","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025030707230113200_r2","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.2146\/ajhp110624","article-title":"Current trends in immunosuppressive therapies for renal transplant recipients","volume":"69","author":"Lee","year":"2012","journal-title":"Am. J. Health Syst. Pharm."},{"key":"2025030707230113200_r3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature08155","article-title":"mTOR regulates memory CD8 T-cell differentiation","volume":"460","author":"Araki","year":"2009","journal-title":"Nature"},{"key":"2025030707230113200_r4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature08097","article-title":"Enhancing CD8 T-cell memory by modulating fatty acid metabolism","volume":"460","author":"Pearce","year":"2009","journal-title":"Nature"},{"key":"2025030707230113200_r5","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.4049\/jimmunol.1001176","article-title":"Cutting edge: rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses","volume":"185","author":"Ferrer","year":"2010","journal-title":"J. Immunol."},{"key":"2025030707230113200_r6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/ni.2005","article-title":"The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2","volume":"12","author":"Delgoffe","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030707230113200_r7","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.immuni.2009.04.014","article-title":"The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment","volume":"30","author":"Delgoffe","year":"2009","journal-title":"Immunity"},{"key":"2025030707230113200_r8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.immuni.2009.10.010","article-title":"The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin","volume":"32","author":"Rao","year":"2010","journal-title":"Immunity"},{"key":"2025030707230113200_r9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s11357-013-9572-5","article-title":"Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice","volume":"36","author":"Kusne","year":"2014","journal-title":"Age (Dordr.)"},{"key":"2025030707230113200_r10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1742-4933-9-17","article-title":"The LCMV gp33-specific memory T cell repertoire narrows with age","volume":"9","author":"Bunztman","year":"2012","journal-title":"Immun. Ageing"},{"key":"2025030707230113200_r11","doi-asserted-by":"crossref","first-page":"16601","DOI":"10.1073\/pnas.1003457107","article-title":"Differential effects of STAT5 and PI3K\/AKT signaling on effector and memory CD8 T-cell survival","volume":"107","author":"Hand","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707230113200_r12","doi-asserted-by":"crossref","first-page":"3402","DOI":"10.4049\/jimmunol.166.5.3402","article-title":"Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection","volume":"166","author":"Pope","year":"2001","journal-title":"J. Immunol."},{"key":"2025030707230113200_r13","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1002\/eji.201041141","article-title":"Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice","volume":"41","author":"Smithey","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025030707230113200_r14","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1084\/jem.20090222","article-title":"Key role of T cell defects in age-related vulnerability to West Nile virus","volume":"206","author":"Brien","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025030707230113200_r15","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.smim.2012.04.008","article-title":"Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans","volume":"24","author":"Solana","year":"2012","journal-title":"Semin. Immunol."},{"key":"2025030707230113200_r16","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1128\/IAI.00207-13","article-title":"Infection with Francisella tularensis LVS clpB leads to an altered yet protective immune response","volume":"81","author":"Barrigan","year":"2013","journal-title":"Infect. Immun."},{"key":"2025030707230113200_r17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4049\/jimmunol.171.1.27","article-title":"Cutting edge: rapid in vivo killing by memory CD8 T cells","volume":"171","author":"Barber","year":"2003","journal-title":"J. Immunol."},{"key":"2025030707230113200_r18","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1002\/eji.200737196","article-title":"Protective capacity and epitope specificity of CD8+ T cells responding to lethal West Nile virus infection","volume":"37","author":"Brien","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025030707230113200_r19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nrmicro2950","article-title":"West Nile virus infection and immunity","volume":"11","author":"Suthar","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"2025030707230113200_r20","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1146\/annurev.immunol.26.021607.090326","article-title":"Monocyte-mediated defense against microbial pathogens","volume":"26","author":"Serbina","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"2025030707230113200_r21","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.immuni.2007.07.010","article-title":"Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor","volume":"27","author":"Joshi","year":"2007","journal-title":"Immunity"},{"key":"2025030707230113200_r22","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.cell.2013.05.016","article-title":"Posttranscriptional control of T cell effector function by aerobic glycolysis","volume":"153","author":"Chang","year":"2013","journal-title":"Cell"},{"key":"2025030707230113200_r23","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1084\/jem.20112607","article-title":"PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells","volume":"209","author":"Finlay","year":"2012","journal-title":"J. Exp. Med."},{"key":"2025030707230113200_r24","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.immuni.2011.12.007","article-title":"Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development","volume":"36","author":"van der Windt","year":"2012","journal-title":"Immunity"},{"key":"2025030707230113200_r25","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.immuni.2010.09.002","article-title":"The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism","volume":"33","author":"Powell","year":"2010","journal-title":"Immunity"},{"key":"2025030707230113200_r26","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.4161\/cc.9.15.12359","article-title":"Fine-tuning CD8+ T cell functional responses: mTOR acts as a rheostat for regulating CD8+ T cell proliferation, survival and differentiation?","volume":"9","author":"Rao","year":"2010","journal-title":"Cell Cycle"},{"key":"2025030707230113200_r27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nri2888","article-title":"Metabolism, migration and memory in cytotoxic T cells","volume":"11","author":"Finlay","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2025030707230113200_r28","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.it.2012.01.010","article-title":"Metabolic pathways in T cell fate and function","volume":"33","author":"Gerriets","year":"2012","journal-title":"Trends Immunol."},{"key":"2025030707230113200_r29","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.4049\/jimmunol.1103365","article-title":"Regulating mammalian target of rapamycin to tune vaccination-induced CD8+ T cell responses for tumor immunity","volume":"188","author":"Li","year":"2012","journal-title":"J. Immunol."},{"key":"2025030707230113200_r30","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1038\/ni.2741","article-title":"The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus","volume":"14","author":"Keating","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025030707230113200_r31","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.immuni.2011.07.010","article-title":"CD8+ T cells: foot soldiers of the immune system","volume":"35","author":"Zhang","year":"2011","journal-title":"Immunity"},{"key":"2025030707230113200_r32","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/nature06322","article-title":"mTOR controls mitochondrial oxidative function through a YY1-PGC-1\u03b1 transcriptional complex","volume":"450","author":"Cunningham","year":"2007","journal-title":"Nature"},{"key":"2025030707230113200_r33","doi-asserted-by":"crossref","first-page":"27643","DOI":"10.1074\/jbc.M603536200","article-title":"The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity","volume":"281","author":"Schieke","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2025030707230113200_r34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/460041a","article-title":"Immunology: a metabolic switch to memory","volume":"460","author":"Prlic","year":"2009","journal-title":"Nature"},{"key":"2025030707230113200_r35","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.immuni.2013.09.015","article-title":"T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming","volume":"39","author":"Yang","year":"2013","journal-title":"Immunity"},{"key":"2025030707230113200_r36","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/ni.2687","article-title":"Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch","volume":"14","author":"Gubser","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025030707230113200_r37","doi-asserted-by":"crossref","first-page":"3299","DOI":"10.4049\/jimmunol.1003613","article-title":"Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets","volume":"186","author":"Michalek","year":"2011","journal-title":"J. Immunol."},{"key":"2025030707230113200_r38","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1172\/JCI69589","article-title":"Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function","volume":"123","author":"Sukumar","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2025030707230113200_r39","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nature08221","article-title":"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice","volume":"460","author":"Harrison","year":"2009","journal-title":"Nature"},{"key":"2025030707230113200_r40","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.1172\/JCI67674","article-title":"Rapamycin extends murine lifespan but has limited effects on aging","volume":"123","author":"Neff","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2025030707230113200_r41","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1474-9726.2012.00832.x","article-title":"Rapamycin slows aging in mice","volume":"11","author":"Wilkinson","year":"2012","journal-title":"Aging Cell"},{"key":"2025030707230113200_r42","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.celrep.2013.07.030","article-title":"Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression","volume":"4","author":"Wu","year":"2013","journal-title":"Cell Rep."},{"key":"2025030707230113200_r43","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.smim.2012.04.004","article-title":"B cell maintenance and function in aging","volume":"24","author":"Kogut","year":"2012","journal-title":"Semin. Immunol."},{"key":"2025030707230113200_r44","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.smim.2012.04.009","article-title":"Age-related changes in CD8 T cell homeostasis and immunity to infection","volume":"24","author":"Nikolich-\u017dugich","year":"2012","journal-title":"Semin. Immunol."},{"key":"2025030707230113200_r45","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.3201\/eid1011.040469","article-title":"Vaccines for women age 50 and older","volume":"10","author":"Gardner","year":"2004","journal-title":"Emerg. Infect. Dis."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/2\/757\/61452682\/1400188.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/2\/757\/61452682\/1400188.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:48:17Z","timestamp":1741333697000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/193\/2\/757\/7956857"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,7,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1400188","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,7]]},"published":{"date-parts":[[2014,7]]}}}