{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:57:02Z","timestamp":1754261822968,"version":"3.37.3"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Sorting nexin 27 is a unique member of the sorting nexin family of proteins that mediates the endosome-to-plasma membrane trafficking of cargos bearing a PSD95\/Dlg1\/ZO-1 (PDZ)\u2013binding motif. In brain, sorting nexin 27 regulates synaptic plasticity, and its dysregulation contributes to cognitive impairment and neuronal degeneration. In T lymphocytes, sorting nexin 27 partners with diacylglycerol kinase \u03b6 to facilitate polarized traffic and signaling at the immune synapse. By silencing sorting nexin 27 expression in a human T-cell line, we demonstrate that sorting nexin 27 is a key regulator of the early T-cell tyrosine-based signaling cascade. Sorting nexin 27 transcriptionally controls CD4 abundance in resting conditions and that of its associated molecule, Lck. This guarantees the adequate recruitment of Lck at the immune synapse, which is indispensable for subsequent activation of tyrosine phosphorylation-regulated events. In contrast, reduced sorting nexin 27 expression enhances NF-\u03baB\u2013dependent induction of CXCR4 and triggers production of lytic enzymes and proinflammatory cytokines. These results provide mechanistic explanation to previously described sorting nexin 27 function in the control of immune synapse organization and indicate that impaired sorting nexin 27 expression contributes to CD4 T-cell dysfunction.<\/jats:p>","DOI":"10.1093\/jleuko\/qiae086","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T19:18:22Z","timestamp":1713813502000},"page":"793-806","source":"Crossref","is-referenced-by-count":1,"title":["Sorting nexin 27\u2013dependent regulation of Lck and CD4 tunes the initial stages of T-cell activation"],"prefix":"10.1093","volume":"116","author":[{"given":"Cristina","family":"Rodriguez-Rodriguez","sequence":"first","affiliation":[{"name":"Department of Immunology and Oncology, Spanish National Centre for Biotechnology (CNB-CSIC), UAM Campus de Cantoblanco, Darwin 3 , 28049 Madrid ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Gonz\u00e1lez-Mancha","sequence":"additional","affiliation":[{"name":"Department of Immunology and Oncology, Spanish National Centre for Biotechnology (CNB-CSIC), UAM Campus de Cantoblanco, Darwin 3 , 28049 Madrid ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ane","family":"Ochoa-Echeverr\u00eda","sequence":"additional","affiliation":[{"name":"Department of Immunology and Oncology, Spanish National Centre for Biotechnology (CNB-CSIC), UAM Campus de Cantoblanco, Darwin 3 , 28049 Madrid ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2762-6241","authenticated-orcid":false,"given":"Isabel","family":"M\u00e9rida","sequence":"additional","affiliation":[{"name":"Department of Immunology and Oncology, Spanish National Centre for Biotechnology (CNB-CSIC), UAM Campus de Cantoblanco, Darwin 3 , 28049 Madrid ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"issue":"2","key":"2024100117255047500_qiae086-B1","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1111\/j.1600-0854.2005.00260.x","article-title":"Sorting nexins\u2014unifying trends and new perspectives","volume":"6","author":"Carlton","year":"2005","journal-title":"Traffic"},{"issue":"7","key":"2024100117255047500_qiae086-B2","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/nrm2427","article-title":"Endosomal sorting and signalling: an emerging role for sorting nexins","volume":"9","author":"Cullen","year":"2008","journal-title":"Nat Rev Mol Cell Biol."},{"issue":"1","key":"2024100117255047500_qiae086-B3","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ncb2374.Sorting","article-title":"Sorting nexins provide diversity for retromer-dependent trafficking events Introduction\u202f: the endosomal network","volume":"14","author":"Cullen","year":"2013","journal-title":"Nat. Cell Biol"},{"issue":"5","key":"2024100117255047500_qiae086-B4","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/ncb2721","article-title":"A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport","volume":"15","author":"Steinberg","year":"2013","journal-title":"Nat. Cell Biol"},{"issue":"20","key":"2024100117255047500_qiae086-B5","doi-asserted-by":"publisher","first-page":"4693","DOI":"10.1242\/jcs.103440","article-title":"The retromer complex-endosomal protein recycling and beyond","volume":"125","author":"Seaman","year":"2012","journal-title":"J. Cell Sci"},{"issue":"1","key":"2024100117255047500_qiae086-B6","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.ajhg.2011.06.001","article-title":"VPS35 mutations in Parkinson disease","volume":"89","author":"Vilari\u00f1o-G\u00fcell","year":"2011","journal-title":"Am J Hum Genet."},{"issue":"1","key":"2024100117255047500_qiae086-B7","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.ajhg.2011.06.008","article-title":"A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease","volume":"89","author":"Zimprich","year":"2011","journal-title":"Am J Hum Genet."},{"issue":"10","key":"2024100117255047500_qiae086-B8","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1038\/nsmb.3290","article-title":"A molecular code for endosomal recycling of phosphorylated cargos by the SNX27-retromer complex","volume":"23","author":"Clairfeuille","year":"2016","journal-title":"Nat Struct Mol Biol."},{"issue":"5","key":"2024100117255047500_qiae086-B9","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.neuron.2013.06.046","article-title":"Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease","volume":"79","author":"Lucin","year":"2013","journal-title":"Neuron"},{"key":"2024100117255047500_qiae086-B10","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1001\/archneur.61.8.1200","article-title":"Loss of apolipoprotein E receptor","volume":"61","author":"Scherzer","year":"2004","journal-title":"Arch Neurol."},{"issue":"6","key":"2024100117255047500_qiae086-B11","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1002\/ana.20667","article-title":"Model-guided microarray implicates the retromer complex in Alzheimer's disease","volume":"58","author":"Small","year":"2005","journal-title":"Ann Neurol."},{"issue":"3","key":"2024100117255047500_qiae086-B12","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/j.celrep.2014.09.037","article-title":"Sorting nexin 27 regulates a\u03b2 production through modulating \u03b3-secretase activity","volume":"9","author":"Wang","year":"2014","journal-title":"Cell Rep"},{"issue":"1","key":"2024100117255047500_qiae086-B13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1002\/ana.25752","article-title":"Dysregulation of the retromer Complex system in down syndrome","volume":"88","author":"Curtis","year":"2020","journal-title":"Ann Neurol."},{"issue":"1","key":"2024100117255047500_qiae086-B14","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/ana.26042","article-title":"Endosome dysregulation in down syndrome: a potential contributor to Alzheimer disease pathology","volume":"90","author":"Filippone","year":"2021","journal-title":"Ann Neurol."},{"issue":"4","key":"2024100117255047500_qiae086-B15","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/nm.3117","article-title":"Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome","volume":"19","author":"Wang","year":"2013","journal-title":"Nat Med."},{"issue":"6","key":"2024100117255047500_qiae086-B16","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1074\/mcp.M700047-MCP200","article-title":"Proteomics identification of sorting nexin 27 as a diacyglycerol kinase \u03b6-associated protein: new diacylglycerol kinase roles in endocytic recycling","volume":"6","author":"Rinc\u00f3n","year":"2007","journal-title":"Mol Cell Proteomics"},{"issue":"5","key":"2024100117255047500_qiae086-B17","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1242\/jcs.072447","article-title":"Translocation dynamics of sorting nexin 27 in activated T cells","volume":"124","author":"Rinc\u00f3n","year":"2011","journal-title":"J. Cell Sci"},{"issue":"8","key":"2024100117255047500_qiae086-B18","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1111\/tra.12492","article-title":"Sorting nexin 27 interactome in T-lymphocytes identifies zona occludens-2 dynamic redistribution at the immune synapse","volume":"18","author":"Tello-Lafoz","year":"2017","journal-title":"Traffic"},{"key":"2024100117255047500_qiae086-B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2021.814570","article-title":"Sorting nexin 27 enables MTOC and secretory machinery translocation to the immune synapse","volume":"12","author":"Gonz\u00e1lez-Mancha","year":"2022","journal-title":"Front Immunol."},{"issue":"11","key":"2024100117255047500_qiae086-B20","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/J.TIBS.2011.06.005","article-title":"Shaping up the membrane: diacylglycerol coordinates spatial orientation of signaling","volume":"36","author":"Almena","year":"2011","journal-title":"Trends Biochem Sci"},{"issue":"2","key":"2024100117255047500_qiae086-B21","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.ceca.2007.03.007","article-title":"Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes","volume":"42","author":"Gwack","year":"2007","journal-title":"Cell Calcium"},{"issue":"18","key":"2024100117255047500_qiae086-B22","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1101\/gad.1102703","article-title":"Transcriptional regulation by calcium, calcineurin, and NFAT","volume":"17","author":"Hogan","year":"2003","journal-title":"Genes Dev"},{"issue":"6","key":"2024100117255047500_qiae086-B23","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/ni.1734","article-title":"Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cells","volume":"10","author":"Quann","year":"2009","journal-title":"Nat Immunol."},{"issue":"29","key":"2024100117255047500_qiae086-B24","doi-asserted-by":"publisher","first-page":"11976","DOI":"10.1073\/pnas.1306180110","article-title":"Diacylglycerol promotes centrosome polarization in T cells via reciprocal localization of dynein and myosin II","volume":"110","author":"Liu","year":"2013","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"7","key":"2024100117255047500_qiae086-B25","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1038\/ni.2033","article-title":"A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells","volume":"12","author":"Quann","year":"2011","journal-title":"Nat Immunol."},{"issue":"360","key":"2024100117255047500_qiae086-B26","doi-asserted-by":"publisher","first-page":"ra82","DOI":"10.1126\/scisignal.2005287.Diacylglycerol","article-title":"Diacylglycerol kinase-\u03b1 controls T cell polarity by shaping diacylglycerol accumulation at the immune synapse","volume":"7","author":"Chauveau","year":"2014","journal-title":"Sci Signal."},{"issue":"1","key":"2024100117255047500_qiae086-B27","doi-asserted-by":"publisher","first-page":"16361","DOI":"10.1038\/s41598-017-16370-w","article-title":"SNX27 links DGK\u03b6 to the control of transcriptional and metabolic programs in T lymphocytes","volume":"7","author":"Tello-Lafoz","year":"2017","journal-title":"Sci Rep."},{"issue":"6","key":"2024100117255047500_qiae086-B28","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/icb.2017.7","article-title":"Predominant contribution of DGK\u03b6 over DGK\u03b1 in the control of PKC\/PDK-1-regulated functions in T cells","volume":"95","author":"\u00c1vila-Flores","year":"2017","journal-title":"Immunol. Cell Biol"},{"issue":"459","key":"2024100117255047500_qiae086-B29","doi-asserted-by":"publisher","first-page":"ra127","DOI":"10.1126\/SCISIGNAL.AAF7714\/SUPPL_FILE\/9_RA127_SM.PDF","article-title":"Diacylglycerol kinase z limits the polarized recruitment of diacylglycerol-enriched organelles to the immune synapse in T cells","volume":"9","author":"Andrada","year":"2016","journal-title":"Sci Signal."},{"issue":"627","key":"2024100117255047500_qiae086-B30","doi-asserted-by":"publisher","first-page":"eaaw8214","DOI":"10.1126\/scisignal.aaw8214","article-title":"Diacylglycerol kinase \u03b6 promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse","volume":"13","author":"Merino-Cort\u00e9s","year":"2020","journal-title":"Sci Signal."},{"issue":"1\u20132","key":"2024100117255047500_qiae086-B31","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.jim.2010.09.020","article-title":"T cell stimulator cells, an efficient and versatile cellular system to assess the role of costimulatory ligands in the activation of human T cells","volume":"362","author":"Leitner","year":"2010","journal-title":"J Immunol Methods."},{"issue":"9","key":"2024100117255047500_qiae086-B32","doi-asserted-by":"publisher","first-page":"5805","DOI":"10.4049\/jimmunol.180.9.5805","article-title":"Lck-Dependent tyrosine phosphorylation of diacylglycerol kinase \u03b1 regulates its membrane association in T cells","volume":"180","author":"Merino","year":"2008","journal-title":"J Immunol."},{"issue":"10","key":"2024100117255047500_qiae086-B33","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.1242\/jcs.118513","article-title":"Transient PKC\u03b1 shuttling to the immunological synapse is governed by DGK\u03b6 and regulates L-selectin shedding","volume":"126","author":"Gharbi","year":"2013","journal-title":"J Cell Sci"},{"issue":"4","key":"2024100117255047500_qiae086-B34","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1083\/jcb.201004060","article-title":"SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane","volume":"190","author":"Lauffer","year":"2010","journal-title":"J Cell Biol"},{"issue":"9","key":"2024100117255047500_qiae086-B35","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1182\/blood-2008-02-141275","article-title":"CD4-CCR5 interaction in intracellular compartments contributes to receptor expression at the cell surface","volume":"113","author":"Achour","year":"2009","journal-title":"Blood"},{"key":"2024100117255047500_qiae086-B36","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev.immunol.021908.132706.T","article-title":"T cell activation","volume":"27","author":"Smith-garvin","year":"2009","journal-title":"Immunology"},{"issue":"21","key":"2024100117255047500_qiae086-B37","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1128\/MCB.24.21.9668-9681.2004","article-title":"Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance","volume":"24","author":"Liu","year":"9668","journal-title":"Mol Cell Biol."},{"issue":"34","key":"2024100117255047500_qiae086-B38","doi-asserted-by":"publisher","first-page":"14157","DOI":"10.1073\/PNAS.1107747108\/-\/DCSUPPLEMENTAL\/PNAS.201107747SI.PDF","article-title":"Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85\u03b1 Src homology-2 domains","volume":"108","author":"Lee","year":"2011","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"6","key":"2024100117255047500_qiae086-B39","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/J.IMMUNI.2010.05.011","article-title":"Constitutively active lck kinase in T cells drives antigen receptor signal transduction","volume":"32","author":"Nika","year":"2010","journal-title":"Immunity"},{"issue":"11","key":"2024100117255047500_qiae086-B40","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1084\/JEM.20130150","article-title":"Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse","volume":"210","author":"Soares","year":"2415","journal-title":"J Exp Med."},{"issue":"7","key":"2024100117255047500_qiae086-B41","doi-asserted-by":"publisher","first-page":"2967","DOI":"10.4049\/JIMMUNOL.1600671","article-title":"Rab11-FIP3 regulation of lck endosomal traffic controls TCR signal transduction","volume":"198","author":"Bouchet","year":"2017","journal-title":"J Immunol."},{"key":"2024100117255047500_qiae086-B42","doi-asserted-by":"publisher","first-page":"626095","DOI":"10.3389\/FCELL.2021.626095","article-title":"How the discovery of the CD4\/CD8-p56lck complexes changed immunology and immunotherapy","volume":"9","author":"Rudd","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"2","key":"2024100117255047500_qiae086-B43","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1002\/j.1460-2075.1990.tb08127.x","article-title":"Structural features of the cytoplasmic region of CD4 required for internalization","volume":"9","author":"Shin","year":"1990","journal-title":"EMBO J"},{"issue":"16","key":"2024100117255047500_qiae086-B44","doi-asserted-by":"publisher","first-page":"10658","DOI":"10.1016\/s0021-9258(18)99274-4","article-title":"Phosphorylation-dependent down-modulation of CD4 requires a specific structure within the cytoplasmic domain of CD4","volume":"266","author":"Shin","year":"1991","journal-title":"J Biol Chem."},{"issue":"3","key":"2024100117255047500_qiae086-B45","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1091\/mbc.10.3.677","article-title":"Cluster of differentiation antigen 4 (CD4) endocytosis and adaptor complex binding require activation of the CD4 endocytosis signal by serine phosphorylation","volume":"10","author":"Pitcher","year":"1999","journal-title":"Mol Biol Cell."},{"issue":"20","key":"2024100117255047500_qiae086-B46","doi-asserted-by":"publisher","first-page":"14176","DOI":"10.1074\/JBC.274.20.14176","article-title":"Phorbol ester-induced disruption of the CD4-lck complex occurs within a detergent-resistant microdomain of the plasma membrane. Involvement of the translocation of activated protein kinase C isoforms","volume":"274","author":"Parolini","year":"1999","journal-title":"J Biol Chem."},{"issue":"3","key":"2024100117255047500_qiae086-B47","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1083\/JCB.145.3.457","article-title":"Trafficking of an acylated cytosolic protein: newly synthesized p56lck travels to the plasma membrane via the exocytic pathway","volume":"145","author":"Bijlmakers","year":"1999","journal-title":"J. Cell Biol"},{"issue":"4","key":"2024100117255047500_qiae086-B48","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1002\/J.1460-2075.1994.TB06320.X","article-title":"Association of p56lck with the cytoplasmic domain of CD4 modulates HIV-1 expression","volume":"13","author":"Tremblay","year":"1994","journal-title":"EMBO J"},{"issue":"4","key":"2024100117255047500_qiae086-B49","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.bbamem.2006.11.002","article-title":"Regulation of CXCR4 signaling","volume":"1768","author":"Busillo","year":"2007","journal-title":"Biochim. Biophys. Acta\u2014Biomembr"},{"issue":"4","key":"2024100117255047500_qiae086-B50","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1111\/J.1474-9726.2012.00830.X","article-title":"Altered regulation of CXCR4 expression during aging contributes to increased CXCL12-dependent chemotactic migration of CD4(+) T cells","volume":"11","author":"Can\u00e9","year":"2012","journal-title":"Aging Cell"},{"issue":"1","key":"2024100117255047500_qiae086-B51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12977-015-0213-1","article-title":"Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced CD4 and enhanced CXCR4 and FAS surface expression levels","volume":"12","author":"Heigele","year":"2015","journal-title":"Retrovirology"},{"issue":"24","key":"2024100117255047500_qiae086-B52","doi-asserted-by":"publisher","first-page":"21631","DOI":"10.1074\/jbc.M300609200","article-title":"NF-\u03baB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4","volume":"278","author":"Helbig","year":"2003","journal-title":"J Biol Chem."},{"issue":"6","key":"2024100117255047500_qiae086-B53","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/S41590-021-00927-Z","article-title":"Hallmarks of T cell aging","volume":"22","author":"Mittelbrunn","year":"2021","journal-title":"Nat Immunol."},{"issue":"5","key":"2024100117255047500_qiae086-B54","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/nri.2017.142","article-title":"NF-\u03baB, inflammation, immunity and cancer: coming of age","volume":"18","author":"Taniguchi","year":"2018","journal-title":"Nat Rev Immunol."},{"issue":"8","key":"2024100117255047500_qiae086-B55","doi-asserted-by":"publisher","first-page":"1967","DOI":"10.1002\/EJI.1830210828","article-title":"The tyrosine kinase activity of p56lck is increased in human T cells activated via CD2","volume":"21","author":"Danielian","year":"1991","journal-title":"Eur J Immunol."},{"issue":"9","key":"2024100117255047500_qiae086-B56","doi-asserted-by":"publisher","first-page":"4279","DOI":"10.1126\/SCIENCE.7509083","article-title":"Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases","volume":"193","author":"Iwashima","year":"1994","journal-title":"Science (80-.)"},{"issue":"22","key":"2024100117255047500_qiae086-B57","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1128\/MCB.00168-06","article-title":"Lck regulates the threshold of activation in primary T cells, while both lck and fyn contribute to the magnitude of the extracellular signal-related kinase response","volume":"26","author":"Lovatt","year":"8655","journal-title":"Mol Cell Biol."},{"issue":"4","key":"2024100117255047500_qiae086-B58","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/0092-8674(92)90428-F","article-title":"Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor","volume":"70","author":"Straus","year":"1992","journal-title":"Cell"},{"issue":"1","key":"2024100117255047500_qiae086-B59","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/S41590-022-01366-0","article-title":"Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells","volume":"24","author":"Horkova","year":"2023","journal-title":"Nat Immunol."},{"key":"2024100117255047500_qiae086-B60","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.coi.2012.02.002","article-title":"CD4-CD8 differentiation in the thymus: connecting circuits and building memories this review comes from a themed issue on lymphocyte development edited","volume":"24","author":"Xiong","year":"2012","journal-title":"Curr Opin Immunol."},{"issue":"9","key":"2024100117255047500_qiae086-B61","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/S41577-019-0180-1","article-title":"Mechanisms underlying T cell ageing","volume":"19","author":"Goronzy","year":"2019","journal-title":"Nat Rev Immunol."},{"issue":"3","key":"2024100117255047500_qiae086-B62","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1006\/clin.1996.0031","article-title":"Immune dysfunction in Down's syndrome: primary immune deficiency or early senescence of the immune system?","volume":"78","author":"Cuadrado","year":"1996","journal-title":"Clin Immunol Immunopathol."},{"key":"2024100117255047500_qiae086-B63","doi-asserted-by":"publisher","first-page":"111824","DOI":"10.1016\/j.mad.2023.111824","article-title":"Cellular senescence and premature aging in down syndrome","volume":"212","author":"Peng","year":"2023","journal-title":"Mech. Ageing Dev"},{"issue":"627","key":"2024100117255047500_qiae086-B64","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1126\/scitranslmed.abi4888","article-title":"Deep immune phenotyping reveals similarities between aging, down syndrome, and autoimmunity","volume":"14","author":"Lambert","year":"4888","journal-title":"Sci Transl Med."},{"issue":"7","key":"2024100117255047500_qiae086-B65","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1016\/j.celrep.2019.10.038","article-title":"Mass cytometry reveals global immune remodeling with multi-lineage hypersensitivity to type I interferon in down syndrome","volume":"29","author":"Waugh","year":"2019","journal-title":"Cell Rep"},{"issue":"48","key":"2024100117255047500_qiae086-B66","doi-asserted-by":"publisher","first-page":"24231","DOI":"10.1073\/pnas.1908129116","article-title":"Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity","volume":"116","author":"Araya","year":"2019","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"7","key":"2024100117255047500_qiae086-B67","doi-asserted-by":"publisher","first-page":"4173","DOI":"10.4049\/jimmunol.176.7.4173","article-title":"A novel NF-\u03baB binding site controls human granzyme B gene transcription","volume":"176","author":"Huang","year":"2006","journal-title":"J Immunol."},{"key":"2024100117255047500_qiae086-B68","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.cyto.2016.08.003","article-title":"TNF activity and T cells","volume":"101","author":"Mehta","year":"2018","journal-title":"Cytokine"},{"key":"2024100117255047500_qiae086-B69","doi-asserted-by":"publisher","first-page":"72","DOI":"10.3389\/fimmu.2013.00072","article-title":"Elevated granzyme B in cytotoxic lymphocytes is a signature of immune activation in hemophagocytic lymphohistiocytosis","volume":"4","author":"Mellor-Heineke","year":"2013","journal-title":"Front Immunol."},{"issue":"3","key":"2024100117255047500_qiae086-B70","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1002\/1097-0029(20000801)50:3&lt;196::AID-JEMT3&gt;3.0.CO;2-9","article-title":"Role of TNF in lymphocyte-mediated cytotoxicity","volume":"50","author":"Smyth","year":"2000","journal-title":"Microsc Res Tech."},{"key":"2024100117255047500_qiae086-B71","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.3389\/fimmu.2022.867189","article-title":"The era of cytotoxic CD4 T cells","volume":"13","author":"Cenerenti","year":"2022","journal-title":"Front Immunol."},{"key":"2024100117255047500_qiae086-B72","doi-asserted-by":"publisher","first-page":"194","DOI":"10.3389\/fimmu.2017.00194","article-title":"CD4 CTL, a cytotoxic subset of CD4+ T cells, their differentiation and function","volume":"8","author":"Takeuchi","year":"2017","journal-title":"Front Immunol."},{"issue":"11","key":"2024100117255047500_qiae086-B73","doi-asserted-by":"publisher","first-page":"5954","DOI":"10.4049\/jimmunol.168.11.5954","article-title":"Characterization of CD4+ CTLs ex vivo","volume":"168","author":"Appay","year":"2002","journal-title":"J Immunol."},{"issue":"8","key":"2024100117255047500_qiae086-B74","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1111\/j.1365-2893.2006.00723.x","article-title":"Cytotoxic CD4+ T cells in viral hepatitis","volume":"13","author":"Aslan","year":"2006","journal-title":"J. Viral Hepat"},{"key":"2024100117255047500_qiae086-B75","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3389\/fimmu.2017.00019","article-title":"Cytotoxic CD4 T cells-friend or foe during viral infection?","volume":"8","author":"Juno","year":"2017","journal-title":"Front Immunol."},{"key":"2024100117255047500_qiae086-B76","doi-asserted-by":"publisher","first-page":"954602","DOI":"10.1155\/2011\/954602","article-title":"Cytotoxic CD4 T cells in antiviral immunity","volume":"2011","author":"Marshall","year":"2011","journal-title":"J Biomed Biotechnol"},{"issue":"5","key":"2024100117255047500_qiae086-B77","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1016\/j.cell.2020.10.001","article-title":"Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19","volume":"183","author":"Meckiff","year":"2020","journal-title":"Cell"},{"issue":"6","key":"2024100117255047500_qiae086-B78","doi-asserted-by":"publisher","first-page":"2238","DOI":"10.1182\/blood-2003-08-2765","article-title":"Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection","volume":"103","author":"Zaunders","year":"2004","journal-title":"Blood"},{"issue":"10","key":"2024100117255047500_qiae086-B79","doi-asserted-by":"publisher","first-page":"6514","DOI":"10.4049\/jimmunol.179.10.6514","article-title":"CD4 + CD28null t cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation","volume":"179","author":"Thewissen","year":"2007","journal-title":"J Immunol."},{"issue":"3","key":"2024100117255047500_qiae086-B80","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.coi.2008.03.007","article-title":"Cytotoxic human CD4+ T cells","volume":"20","author":"van de Berg","year":"2008","journal-title":"Curr Opin Immunol."},{"issue":"3","key":"2024100117255047500_qiae086-B81","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1084\/jem.20091918","article-title":"Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts","volume":"207","author":"Quezada","year":"2010","journal-title":"J Exp Med."},{"issue":"3","key":"2024100117255047500_qiae086-B82","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1084\/jem.20091921","article-title":"Naive tumor-specific CD4+ T cells differentiated in vivo eradicate established melanoma","volume":"207","author":"Xie","year":"2010","journal-title":"J Exp Med."},{"issue":"4","key":"2024100117255047500_qiae086-B83","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s11357-010-9200-6","article-title":"NKG2D expression in CD4+ T lymphocytes as a marker of senescence in the aged immune system","volume":"33","author":"Alonso-Arias","year":"2011","journal-title":"Age (Omaha)"},{"issue":"8","key":"2024100117255047500_qiae086-B84","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1128\/mcb.01044-10","article-title":"Deficiency of sorting nexin 27 (SNX27) leads to growth retardation and elevated levels of N -methyl- d -aspartate receptor 2C (NR2C)","volume":"31","author":"Cai","year":"2011","journal-title":"Mol Cell Biol."},{"issue":"9","key":"2024100117255047500_qiae086-B85","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.7326\/M22-1460","article-title":"Good publication practice (GPP) guidelines for company-sponsored biomedical research: 2022 update","volume":"175","author":"DeTora","year":"2022","journal-title":"Ann Intern Med."}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jleukbio\/advance-article-pdf\/doi\/10.1093\/jleuko\/qiae086\/57464746\/qiae086.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/116\/4\/793\/59483692\/qiae086.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/116\/4\/793\/59483692\/qiae086.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T17:25:59Z","timestamp":1727803559000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/116\/4\/793\/7656002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,22]]},"references-count":85,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4,22]]},"published-print":{"date-parts":[[2024,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jleuko\/qiae086","relation":{},"ISSN":["1938-3673"],"issn-type":[{"type":"electronic","value":"1938-3673"}],"subject":[],"published-other":{"date-parts":[[2024,10]]},"published":{"date-parts":[[2024,4,22]]}}}