{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:54:07Z","timestamp":1790952847060,"version":"4.1.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"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>Background<\/jats:title><jats:p>Memory CD8<jats:sup>+<\/jats:sup> T cells sense inflammation and rapidly produce interferon-\u03b3 (IFN-\u03b3) independent of cognate antigens. This innate-like property, called bystander activation, is involved in early host defense before the antigen-specific memory response. However, the molecular mechanisms underlying this activation remain unknown. Retinoic acid receptor-related orphan receptor \u03b1 (ROR\u03b1) belongs to the nuclear receptor family and regulates gene transcription in ligand-dependent manner. Although ROR\u03b1 is highly expressed in memory CD8<jats:sup>+<\/jats:sup> T cells, its functional relevance has not been investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Primary and secondary memory T cells that are sufficient or deficient of ROR\u03b1 were induced by adoptive transfer of na\u00efve OT-I T cells to recipient mice and subsequent infection with <jats:italic>Listeria monocytogenes<\/jats:italic> expressing ovalbumin (LM-OVA). ROR\u03b1 expression in memory T cells was examined by quantitative PCR. The target genes of ROR\u03b1 in memory T cells were explored by RNA-sequencing and verified by ROR\u03b1 overexpression in postactivated T cells. The impact of ROR\u03b1-deficiency on bystander activation was assessed by stimulating memory T cells with inflammatory cytokines <jats:italic>in vitro<\/jats:italic> or injecting lipopolysaccharide (LPS) into mice bearing memory T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ROR\u03b1 expression was remarkably elevated in secondary memory CD8<jats:sup>+<\/jats:sup> T cells along with the enrichment of effector-like memory T cells. ROR\u03b1 primarily acted as a transcription factor in regulating the gene expression of the TL1A receptor. ROR\u03b1 deficiency abrogated the IFN-\u03b3 production by memory CD8<jats:sup>+<\/jats:sup> T cells in response to IL-12 + TL1A <jats:italic>in vitro<\/jats:italic> and diminished the bystander response to LPS-induced inflammation <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study revealed a regulatory mechanism of bystander activation. The findings also improve our understanding of how memory T cells increase their immediate protective capacity through repeated infections and vaccinations.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1647746","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T12:33:12Z","timestamp":1755174792000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Retinoic acid receptor-related orphan receptor \u03b1 regulates bystander activation of memory CD8+ T cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Zimeng","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Kozai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironobu","family":"Mita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroto","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Mizuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Takada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1126\/science.272.5258.54","article-title":"Immunological memory and protective immunity: understanding their relation","volume":"272","author":"Ahmed","year":"1996","journal-title":"Sci (1979)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.20.100101.151926","article-title":"T cell memory","volume":"20","author":"Sprent","year":"2002","journal-title":"Annu Rev Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.10.008","article-title":"From vaccines to memory and back","volume":"33","author":"Sallusto","year":"2010","journal-title":"Immunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031051","article-title":"Memory CD8+ T Cells Provide Innate Immune Protection against Listeria monocytogenes in the Absence of Cognate Antigen","volume":"198","author":"Berg","year":"2003","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.11.6873","article-title":"Activation of virus-specific CD8+ T cells by lipopolysaccharide-induced IL-12 and IL-18","volume":"173","author":"Rau\u00e9","year":"2004","journal-title":"J Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.2.1097","article-title":"Bystander activation of CD8+ T cells contributes to the rapid production of IFN-\u03b3 in response to bacterial pathogens","volume":"166","author":"Lertmemongkolchai","year":"2001","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.immuni.2010.06.016","article-title":"Type I interferons regulate cytolytic activity of memory CD8+ T cells in the lung airways during respiratory virus challenge","volume":"33","author":"Kohlmeier","year":"2010","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.02.020","article-title":"Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner","volume":"3","author":"Chu","year":"2013","journal-title":"Cell Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4236","DOI":"10.1016\/j.celrep.2019.11.103","article-title":"Bystander activation of pulmonary trm cells attenuates the severity of bacterial pneumonia by enhancing neutrophil recruitment","volume":"29","author":"Ge","year":"2019","journal-title":"Cell Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000937","article-title":"The ugly duckling turned to swan: A change in perception of bystander-activated memory CD8 T cells","volume":"206","author":"Maurice","year":"2021","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41590-021-00985-3","article-title":"Significance of bystander T cell activation in microbial infection","volume":"23","author":"Lee","year":"2022","journal-title":"Nat Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/srep18022","article-title":"Antigen-dependent and \u2013independent contributions to primary memory CD8 T cell activation and protection following infection","volume":"5","author":"Martin","year":"2015","journal-title":"Sci Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI162800","article-title":"Memory T cells possess an innate-like function in local protection from mucosal infection","volume":"133","author":"Arkatkar","year":"2023","journal-title":"J Clin Invest"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.06.020","article-title":"Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease","volume":"21","author":"Meresse","year":"2004","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e1003970","DOI":"10.1371\/journal.ppat.1003970","article-title":"Engagement of NKG2D on Bystander Memory CD8 T Cells Promotes Increased Immunopathology following Leishmania major Infection","volume":"10","author":"Crosby","year":"2014","journal-title":"PloS Pathog"},{"key":"B16","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.immuni.2017.11.025","article-title":"Innate-like cytotoxic function of bystander-activated CD8+ T cells is associated with liver injury in acute hepatitis A","volume":"48","author":"Kim","year":"2018","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00634","article-title":"Time and antigen-stimulation history influence memory CD8 T cell bystander responses","volume":"8","author":"Martin","year":"2017","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"4987","DOI":"10.1038\/s41467-019-12980-2","article-title":"CXCR3 enables recruitment and site-specific bystander activation of memory CD8+ T cells","volume":"10","author":"Maurice","year":"2019","journal-title":"Nat Commun"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2024.06.10.598293","DOI":"10.1101\/2024.06.10.598293","article-title":"Steady-state, therapeutic, and helminth-induced IL-4 compromise protective CD8 T cell bystander activation","author":"Maurice","year":"2024","journal-title":"bioRxiv"},{"key":"B20","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nrd4100","article-title":"REV-ERB and ROR nuclear receptors as drug targets","volume":"13","author":"Kojetin","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"B21","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.cmet.2013.12.009","article-title":"The therapeutic potential of nuclear receptor modulators for treatment of metabolic disorders: PPAR\u03b3, RORs, and rev-erbs","volume":"19","author":"Marciano","year":"2014","journal-title":"Cell Metab"},{"key":"B22","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.immuni.2007.11.016","article-title":"T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR\u03b1 and ROR\u03b3","volume":"28","author":"Yang","year":"2008","journal-title":"Immunity"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.06.012","article-title":"Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation","volume":"37","author":"Halim","year":"2012","journal-title":"Immunity"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071733","article-title":"ROR\u03b1 Regulates cholesterol metabolism of CD8+ T cells for anticancer immunity","volume":"12","author":"Lee","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12406","article-title":"ROR agonist hampers the proliferation and survival of postactivated CD8 + T cells through the downregulation of cholesterol synthesis-related genes","volume":"99","author":"Cai","year":"2021","journal-title":"Immunol Cell Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/0092-8674(94)90169-4","article-title":"T cell receptor antagonist peptides induce positive selection","volume":"76","author":"Hogquist","year":"1994","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/BF00364270","article-title":"Genetic nomenclature for loci controlling mouse lymphocyte antigens","volume":"25","author":"Morse","year":"1987","journal-title":"Immunogenetics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.22.7.743","article-title":"Developmental mechanism for changes in cerebellum of \u201cstaggerer\u201d mouse, a neurological mutant of genetic origin","volume":"22","author":"Yoon","year":"1972","journal-title":"Neurology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060995","article-title":"Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection","volume":"203","author":"Vezys","year":"2006","journal-title":"J Exp Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.11.6791","article-title":"Dynamic regulation of IFN-\u03b3 Signaling in antigen-specific CD8+ T cells responding to infection","volume":"174","author":"Haring","year":"2005","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.05.009","article-title":"Effector-like CD8+ T cells in the memory population mediate potent protective immunity","volume":"38","author":"Olson","year":"2013","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/379736a0","article-title":"Disruption of the nuclear hormone receptor ROR\u03b1 in staggerer mice","volume":"379","author":"Hamilton","year":"1996","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks630","article-title":"ROR\u03b3 directly regulates the circadian expression of clock genes and downstream targets in vivo","volume":"40","author":"Takeda","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.8.4985","article-title":"Dominant role for TL1A\/DR3 pathway in IL-12 plus IL-18-induced IFN-\u03b3 Production by peripheral blood and mucosal CCR9+ T lymphocytes","volume":"174","author":"Papadakis","year":"2005","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.04.037","article-title":"TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation","volume":"135","author":"Takedatsu","year":"2008","journal-title":"Gastroenterology"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.05.029","article-title":"Inflammatory monocytes activate memory CD8+ T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion","volume":"37","author":"Soudja","year":"2012","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","first-page":"e1006566","DOI":"10.1371\/journal.ppat.1006566","article-title":"T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria","volume":"13","author":"Pham","year":"2017","journal-title":"PloS Pathog"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1203543109","article-title":"Regulation of innate CD8 + T-cell activation mediated by cytokines","volume":"109","author":"Freeman","year":"2012","journal-title":"Proc Natl Acad Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052237","article-title":"Secondary memory CD8+ T cells are more protective but slower to acquire a central\u2013memory phenotype","volume":"203","author":"Jabbari","year":"2006","journal-title":"J Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.02.010","article-title":"Understanding subset diversity in T cell memory","volume":"48","author":"Jameson","year":"2018","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02692","article-title":"Defining memory CD8 T cell","volume":"9","author":"Martin","year":"2018","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.2.831","article-title":"Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination","volume":"177","author":"Masopust","year":"2006","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071364","article-title":"TL1A\u2013DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease","volume":"205","author":"Pappu","year":"2008","journal-title":"J Exp Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2009.263","article-title":"Immunology: TL1A in the inflammatory network in autoimmune diseases","volume":"6","author":"Bayry","year":"2010","journal-title":"Nat Rev Rheumatol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.semarthrit.2015.02.007","article-title":"The TL1A\/DR3\/DcR3 pathway in autoimmune rheumatic diseases","volume":"45","author":"Siakavellas","year":"2015","journal-title":"Semin Arthritis Rheum"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901512","article-title":"KLRG1+ Memory CD8 T cells combine properties of short-lived effectors and long-lived memory","volume":"205","author":"Renkema","year":"2020","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2008571117","article-title":"Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population","volume":"117","author":"Milner","year":"2020","journal-title":"Proc Natl Acad Sci"},{"key":"B48","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/s41467-020-20385-9","article-title":"Genetic and pharmacological inhibition of the nuclear receptor ROR\u03b1 regulates TH17 driven inflammatory disorders","volume":"12","author":"Wang","year":"2021","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1647746\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T12:33:12Z","timestamp":1755174792000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1647746\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,14]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2025.1647746"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1647746","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,14]]},"article-number":"1647746"}}