{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T17:08:56Z","timestamp":1779469736737,"version":"3.53.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1R21AI119137-01A1"],"award-info":[{"award-number":["1R21AI119137-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1R21AI151333-01A1"],"award-info":[{"award-number":["1R21AI151333-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>How T cell expansion, migration, and differentiation are coordinately controlled remains incompletely understood. The KLF2 transcription factor is critical for expression of cell surface molecules, which control lymphocyte traffic, and has been postulated to function as a mediator of T cell quiescence. KLF2 expression is rapidly and transiently silenced in activated T (and other) cells via proteolytic degradation and transcriptional silencing, but why recently activated T cells need to turn off KLF2 expression has remained unknown. Here, functions of transient KLF2 loss have been investigated using a novel mouse model in which expression of a KLF2 point mutant which cannot be proteolytically degraded or transcriptionally silenced is turned on by cre-mediated recombination, such that KLF2 expression and function is continuously maintained in T cells. In response to infection with LCMV, generation of CD4 effector T cells was only slightly decreased. In contrast, generation of CD8 effector T cells was sharply reduced, an effect which was intrinsic to CD8 T cells. Despite this, CD8 T cell proliferation in vitro was only modestly inhibited by constitutive KLF2 expression. These findings document an essential requirement for KLF2 downregulation in expansion of CD8 T cells in vivo, identify unanticipated differences between CD4 and CD8 T cells in their requirements for KLF2 downregulation, and suggest that mechanisms distinct from repression of proliferation underlie the failure of activated CD8 T cells to expand in response to viral infection.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag008","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:54:08Z","timestamp":1773827648000},"source":"Crossref","is-referenced-by-count":0,"title":["Transient loss of KLF2 expression is essential for CD8 effector T cell expansion"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0256-3005","authenticated-orcid":false,"given":"Geoffrey S","family":"Kansas","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"2026052212182517500_vkag008-B1","doi-asserted-by":"crossref","first-page":"148027","DOI":"10.1016\/j.gene.2023.148027","article-title":"The kruppel-like factor (KLF) family, diseases, and physiological events","volume":"895","author":"Yuce","year":"2024","journal-title":"Gene"},{"key":"2026052212182517500_vkag008-B2","doi-asserted-by":"crossref","first-page":"4404","DOI":"10.1182\/blood-2010-05-285353","article-title":"Role of Kruppel-like factors in leukocyte development, function, and disease","volume":"116","author":"Cao","year":"2010","journal-title":"Blood"},{"key":"2026052212182517500_vkag008-B3","doi-asserted-by":"crossref","first-page":"521","DOI":"10.4049\/jimmunol.1101530","article-title":"Kruppel-like factors in lymphocyte biology","volume":"188","author":"Hart","year":"2012","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B4","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.4049\/jimmunol.178.12.7632","article-title":"Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription","volume":"178","author":"Bai","year":"2007","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B5","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/nature04882","article-title":"Kruppel-like factor 2 regulates thymocyte and T-cell migration","volume":"442","author":"Carlson","year":"2006","journal-title":"Nature"},{"key":"2026052212182517500_vkag008-B6","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ni.1689","article-title":"Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor","volume":"10","author":"Kerdiles","year":"2009","journal-title":"Nat Immunol"},{"key":"2026052212182517500_vkag008-B7","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1073\/pnas.1013168108","article-title":"Kruppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation, and trafficking molecule expression","volume":"108","author":"Hart","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026052212182517500_vkag008-B8","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.immuni.2009.05.011","article-title":"KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors","volume":"31","author":"Weinreich","year":"2009","journal-title":"Immunity"},{"key":"2026052212182517500_vkag008-B9","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1126\/science.277.5334.1986","article-title":"LKLF: A transcriptional regulator of single-positive T cell quiescence and survival","volume":"277","author":"Kuo","year":"1997","journal-title":"Science"},{"key":"2026052212182517500_vkag008-B10","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/90633","article-title":"Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway","volume":"2","author":"Buckley","year":"2001","journal-title":"Nat Immunol"},{"key":"2026052212182517500_vkag008-B11","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.bbrc.2004.02.033","article-title":"WWP1-dependent ubiquitination and degradation of the lung Kruppel-like factor, KLF2","volume":"316","author":"Zhang","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"key":"2026052212182517500_vkag008-B12","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.bbrc.2011.03.016","article-title":"Smurf1 ubiquitin ligase targets Kruppel-like factor KLF2 for ubiquitination and degradation in human lung cancer H1299 cells","volume":"407","author":"Xie","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"key":"2026052212182517500_vkag008-B13","doi-asserted-by":"crossref","first-page":"775","DOI":"10.4049\/jimmunol.1000094","article-title":"Kruppel-like factor 2 is required for trafficking but not quiescence in postactivated T cells","volume":"186","author":"Takada","year":"2011","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B14","doi-asserted-by":"crossref","first-page":"6725","DOI":"10.4049\/jimmunol.174.11.6725","article-title":"Selective expression of the Cre recombinase in late-stage thymocytes using the distal promoter of the Lck gene","volume":"174","author":"Zhang","year":"2005","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B15","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/ni.1649","article-title":"Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity","volume":"9","author":"Maekawa","year":"2008","journal-title":"Nat Immunol"},{"key":"2026052212182517500_vkag008-B16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1471-213X-1-4","article-title":"Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus","volume":"1","author":"Srinivas","year":"2001","journal-title":"BMC Dev Biol"},{"key":"2026052212182517500_vkag008-B17","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat Neurosci"},{"key":"2026052212182517500_vkag008-B18","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1182\/blood.V91.1.154","article-title":"A novel P-selectin glycoprotein ligand-1 (PSGL-1) monoclonal antibody recognizes an epitope within the tyrosine sulfate motif of human PSGL-1 amd blocks recognition of both P- and L-selectin","volume":"91","author":"Snapp","year":"1998","journal-title":"Blood"},{"key":"2026052212182517500_vkag008-B19","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1083\/jcb.142.1.263","article-title":"Dimerization of P-selectin glycoprotein ligand-1 (PSGL-1) required for optimal recognition of P-selectin","volume":"142","author":"Snapp","year":"1998","journal-title":"J Cell Biol"},{"key":"2026052212182517500_vkag008-B20","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.4049\/jimmunol.2101011","article-title":"Lymphocytic choriomeningitis virus clone 13 infection results in CD8 T cell-mediated host mortality in diacylglycerol kinase alpha-deficient mice","volume":"210","author":"Kudek","year":"2023","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B21","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1002\/eji.201142205","article-title":"From crucial to negligible: functional CD8(+) T-cell responses and their dependence on CD4(+) T-cell help","volume":"42","author":"Wiesel","year":"2012","journal-title":"Eur J Immunol"},{"key":"2026052212182517500_vkag008-B22","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/353180a0","article-title":"Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4","volume":"353","author":"Rahemtulla","year":"1991","journal-title":"Nature"},{"key":"2026052212182517500_vkag008-B23","doi-asserted-by":"crossref","first-page":"9579","DOI":"10.1073\/pnas.1323493111","article-title":"KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production","volume":"111","author":"Pabbisetty","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026052212182517500_vkag008-B24","doi-asserted-by":"crossref","first-page":"eadn2337","DOI":"10.1126\/science.adn2337","article-title":"KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection","volume":"387","author":"Fagerberg","year":"2025","journal-title":"Science"},{"key":"2026052212182517500_vkag008-B25","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41590-023-01685-w","article-title":"FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells","volume":"25","author":"Zhu","year":"2024","journal-title":"Nat Immunol"},{"key":"2026052212182517500_vkag008-B26","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1084\/jem.192.4.549","article-title":"Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells","volume":"192","author":"Cho","year":"2000","journal-title":"J Exp Med"},{"key":"2026052212182517500_vkag008-B27","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1084\/jem.192.4.557","article-title":"Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation","volume":"192","author":"Goldrath","year":"2000","journal-title":"J Exp Med"},{"key":"2026052212182517500_vkag008-B28","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nature04606","article-title":"CD69 acts downstream of interferon-alpha\/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs","volume":"440","author":"Shiow","year":"2006","journal-title":"Nature"},{"key":"2026052212182517500_vkag008-B29","doi-asserted-by":"crossref","first-page":"22328","DOI":"10.1074\/jbc.M110.123299","article-title":"CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function through interaction with membrane helix 4","volume":"285","author":"Bankovich","year":"2010","journal-title":"J Biol Chem"},{"key":"2026052212182517500_vkag008-B30","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.4049\/jimmunol.1402256","article-title":"Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention","volume":"194","author":"Mackay","year":"2015","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B31","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.4049\/jimmunol.163.7.3662","article-title":"Expression of the transcription factor lung Kruppel-like factor is regulated by cytokines and correlates with survival of memory T cells in vitro and in vivo","volume":"163","author":"Schober","year":"1999","journal-title":"J Immunol"},{"key":"2026052212182517500_vkag008-B32","doi-asserted-by":"crossref","first-page":"e77537","DOI":"10.1371\/journal.pone.0077537","article-title":"The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells","volume":"8","author":"Preston","year":"2013","journal-title":"PloS One"},{"key":"2026052212182517500_vkag008-B33","doi-asserted-by":"crossref","first-page":"20453","DOI":"10.1073\/pnas.1008437107","article-title":"Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery","volume":"107","author":"Han","year":"2010","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/3\/vkag008\/67387196\/vkag008.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/3\/vkag008\/67387196\/vkag008.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T16:18:34Z","timestamp":1779466714000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/doi\/10.1093\/jimmun\/vkag008\/8527206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":33,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3,17]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkag008","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2026,3]]},"article-number":"vkag008"}}