{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T10:51:56Z","timestamp":1783421516475,"version":"3.54.6"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL111501, R01HL146645"],"award-info":[{"award-number":["R01HL111501, R01HL146645"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Activation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGK\u03b6), a negative regulator of DAG.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGK\u03b6 blockade or selective activation of ERK.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Upon LCMV CL13 infection, DGK\u03b6 deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGK\u03b6 with ASP1570, a DGK\u03b6-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGK\u03b6 deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT\/mTOR pathway by DGK\u03b6 deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGK\u03b6 KO CD8+ T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Thus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1032113","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T04:26:50Z","timestamp":1669264010000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection"],"prefix":"10.3389","volume":"13","author":[{"given":"Shohei","family":"Harabuchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Bassiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaomi","family":"Takizawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Katada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Kambayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function","volume":"188","author":"Zajac","year":"1998","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.9.1383","article-title":"Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes","volume":"187","author":"Gallimore","year":"1998","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J Virol"},{"key":"B6","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":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2014.12.033","article-title":"T Cell exhaustion during persistent viral infections","author":"Kahan","year":"2015","journal-title":"Virology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.immuni.2019.09.013","article-title":"TCF-1-Centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision","volume":"51","author":"Chen","year":"2019","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/v11020156","article-title":"Immune exhaustion: Past lessons and new insights from lymphocytic choriomeningitis virus","volume":"11","author":"Kahan","year":"2019","journal-title":"Viruses"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1011998107","article-title":"Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression","volume":"107","author":"Bergthaler","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0435-8","article-title":"Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development","volume":"52","author":"Hwang","year":"2020","journal-title":"Exp Mol Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2016.00096","article-title":"The immunomodulatory functions of diacylglycerol kinase zeta","volume":"4","author":"Singh","year":"2016","journal-title":"Front Cell Dev Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.17.11447","article-title":"Mammalian diacylglycerol kinases, a family of lipid kinases with signaling functions","volume":"274","author":"Topham","year":"1999","journal-title":"J Biol Chem"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms14046649","article-title":"Diacylglycerol kinases: regulated controllers of T cell activation, function, and development","volume":"14","author":"Joshi","year":"2013","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1021\/cr1004106","article-title":"Regulation and functions of diacylglycerol kinases","volume":"111","author":"Shulga","year":"2011","journal-title":"Chem Rev"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ni958","article-title":"Enhanced T cell responses due to diacylglycerol kinase zeta deficiency","volume":"4","author":"Zhong","year":"2003","journal-title":"Nat Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203818200","article-title":"Regulation of T cell receptor-induced activation of the ras-ERK pathway by diacylglycerol kinase zeta","volume":"277","author":"Zhong","year":"2002","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.171884","article-title":"Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses","volume":"286","author":"Riese","year":"2011","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/ni1400","article-title":"Disruption of diacylglycerol metabolism impairs the induction of T cell anergy","volume":"7","author":"Olenchock","year":"2006","journal-title":"Nat Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"ra102","DOI":"10.1126\/scisignal.2004373","article-title":"The zeta isoform of diacylglycerol kinase plays a predominant role in regulatory T cell development and TCR-mediated ras signaling","volume":"6","author":"Joshi","year":"2013","journal-title":"Sci Signal"},{"key":"B21","doi-asserted-by":"publisher","first-page":"ra101","DOI":"10.1126\/scisignal.2004411","article-title":"Diacylglycerol kinase zeta limits the generation of natural regulatory T cells","volume":"6","author":"Schmidt","year":"2013","journal-title":"Sci Signal"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80382-9","article-title":"The influence of the MAPK pathway on T cell lineage commitment","volume":"7","author":"Sharp","year":"1997","journal-title":"Immunity"},{"key":"B23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ni.1679","article-title":"Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection","volume":"10","author":"Blackburn","year":"2009","journal-title":"Nat Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)00958-9","article-title":"The sevenmaker gain-of-function mutation in p42 MAP kinase leads to enhanced signalling and reduced sensitivity to dual specificity phosphatase action","volume":"352","author":"Bott","year":"1994","journal-title":"FEBS Letters"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.09.006","article-title":"Molecular signature of CD8+ T cell exhaustion during chronic viral infection","volume":"27","author":"Wherry","year":"2007","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229620","article-title":"Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection","volume":"338","author":"Paley","year":"2012","journal-title":"Science"},{"key":"B27","doi-asserted-by":"publisher","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":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102265","article-title":"Differential regulation of primary and memory CD8 T cell immune responses by diacylglycerol kinases","volume":"188","author":"Shin","year":"2012","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.1700055","article-title":"Diacylglycerol kinase zeta (DGKzeta) and casitas b-lineage proto-oncogene b-deficient mice have similar functional outcomes in T cells but DGKzeta-deficient mice have increased T cell activation and tumor clearance","volume":"2","author":"Wesley","year":"2018","journal-title":"Immunohorizons"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aax3332","article-title":"Diacylglycerol kinase zeta promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms","volume":"12","author":"Singh","year":"2019","journal-title":"Sci Signal"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006080","article-title":"Cell death signaling","volume":"7","author":"Green","year":"2015","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2009.07330.x","article-title":"Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation","volume":"276","author":"Allan","year":"2009","journal-title":"FEBS J"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M301010200","article-title":"Activation of the ERK1\/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, bim","volume":"278","author":"Ley","year":"2003","journal-title":"J Biol Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206261","article-title":"Activation of ERK1\/2 by deltaRaf-1:ER* represses bim expression independently of the JNK or PI3K pathways","volume":"22","author":"Weston","year":"2003","journal-title":"Oncogene"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.03.025","article-title":"Multisite phosphorylation regulates bim stability and apoptotic activity","volume":"30","author":"Hubner","year":"2008","journal-title":"Mol Cell"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.12.020","article-title":"betaTrCP- and Rsk1\/2-mediated degradation of BimEL inhibits apoptosis","volume":"33","author":"Dehan","year":"2009","journal-title":"Mol Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030574","article-title":"Targeting mitochondrial apoptosis to overcome treatment resistance in cancer","volume":"12","author":"Ngoi","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1042\/BST20110647","article-title":"Tumour cell responses to MEK1\/2 inhibitors: acquired resistance and pathway remodelling","volume":"40","author":"Little","year":"2012","journal-title":"Biochem Soc Trans"},{"key":"B39","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1080\/02699050500284218","article-title":"The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions","volume":"24","author":"Yoon","year":"2006","journal-title":"Growth Factors"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.7","article-title":"Genetic analysis of ras signalling pathways in cell proliferation, migration and survival","volume":"29","author":"Drosten","year":"2010","journal-title":"EMBO J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.11.7617","article-title":"The Erk2 MAPK regulates CD8 T cell proliferation and survival","volume":"181","author":"D'Souza","year":"2008","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.22.012703.104554","article-title":"Control of T cell viability","volume":"22","author":"Marrack","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.11.002","article-title":"Homeostasis of naive and memory T cells","volume":"29","author":"Surh","year":"2008","journal-title":"Immunity"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/oncsis.2015.22","article-title":"Diacylglycerol kinase-zeta regulates mTORC1 and lipogenic metabolism in cancer cells through SREBP-1","volume":"4","author":"Torres-Ayuso","year":"2015","journal-title":"Oncogenesis"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-08-300731","article-title":"Negative regulation of mTOR activation by diacylglycerol kinases","volume":"117","author":"Gorentla","year":"2011","journal-title":"Blood"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1172\/JCI26322","article-title":"IKK\/NF-kappaB signaling: Balancing life and death\u2013a new approach to cancer therapy","volume":"115","author":"Luo","year":"2005","journal-title":"J Clin Invest"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2007.04.009","article-title":"Protein kinase c theta (PKCtheta): A key player in T cell life and death","volume":"55","author":"Hayashi","year":"2007","journal-title":"Pharmacol Res"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(06)00046-7","article-title":"Apoptosis: Activate NF-\u03baB or die","volume":"7","author":"Baichwal","year":"1997","journal-title":"Curr Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nature08155","article-title":"mTOR regulates memory CD8 T-cell differentiation","volume":"460","author":"Araki","year":"2009","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.013","article-title":"The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection","volume":"41","author":"Staron","year":"2014","journal-title":"Immunity"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1032113\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T04:26:55Z","timestamp":1669264015000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1032113\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,24]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2022.1032113"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1032113","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,24]]},"article-number":"1032113"}}