{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:38:21Z","timestamp":1790026701492,"version":"4.0.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"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>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>TNFRSF9<\/jats:italic>\n                      gene encodes the costimulatory receptor CD137, also known as 4-1BB, which plays a critical role in sustaining effective cytotoxic T-cell responses. Variants in the\n                      <jats:italic>TNFRSF9<\/jats:italic>\n                      gene are associated with an extremely rare autosomal recessive primary immunodeficiency disorder characterized by recurrent sinopulmonary infections and EBV-induced lymphoproliferation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We report a case siblings exhibiting EBV viremia, recurrent respiratory infections, and Burkitt lymphoma. Whole-exome sequencing (WES) was performed. Sanger sequencing was used to validate the variants. In vitro functional study was performed by western blot, flow cytometry assays and luciferase assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetic analysis identified a novel missense variant in the\n                      <jats:italic>TNFRSF9<\/jats:italic>\n                      gene (NM_001561.5: c.359G&amp;gt;C, p.C120S). Functional analysis in vitro demonstrated that this variant decreased the expression of TNFRSF9 both mRNA and protein levels. Western blot analysis revealed a significant decrease in phosphorylated-AKT. Luciferase assays showed that the p.C120S variant diminished the activity of the NF-\u03baB pathway. Immunophenotyping of the patient\u2019s peripheral blood revealed a significant reduction in CD27+ memory B cells, which are critical for long-term humoral immunity. Additionally, there was a notable decrease in IFN-\u03b3 secretion in CD8+ T cells, suggesting impaired cytotoxic T-cell function. These findings align with the clinical presentation of immunodeficiency and lymphoproliferation observed in the patients. We also reviewed 9 previously reported patients with homozygous or compound heterozygous\n                      <jats:italic>TNFRSF9<\/jats:italic>\n                      variants. The clinical manifestations among these patients were highly heterogeneous, ranging from asymptomatic to malignancies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      In summary, we identified a novel\n                      <jats:italic>TNFRSF9<\/jats:italic>\n                      variant associated with immunodeficiency and lymphoproliferation, supported by functional evidence demonstrating its impact on gene expression, AKT and NF-\u03baB signaling pathways, and immune cell function. Our findings expand the mutation spectrum of the\n                      <jats:italic>TNFRSF9<\/jats:italic>\n                      gene and provide new insights into the molecular mechanisms underlying this rare immunodeficiency disorder.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1605221","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T05:31:23Z","timestamp":1754458283000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Clinical and functional characterization of a novel TNFRSF9 variant causing immune dysregulation with predisposition to EBV-driven lymphomagenesis"],"prefix":"10.3389","volume":"16","author":[{"given":"Peiwei","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhui","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuelian","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161846","article-title":"Human immunity against EBV-lessons from the clinic","volume":"214","author":"Tangye","year":"2017","journal-title":"J Exp Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01103","article-title":"Inherited immunodeficiencies with high predisposition to epstein-barr virus-driven lymphoproliferative diseases","volume":"9","author":"Latour","year":"2018","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1146\/annurev-immunol-032414-112326","article-title":"The immunology of Epstein-Barr virus-induced disease","volume":"33","author":"Taylor","year":"2015","journal-title":"Annu Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e1448","DOI":"10.1002\/cti2.1448","article-title":"CD137 deficiency because of two novel biallelic TNFRSF9 mutations in a patient presenting with severe EBV-associated lymphoproliferative disease","volume":"12","author":"Shen","year":"2023","journal-title":"Clin Transl Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.003176","article-title":"Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier","volume":"293","author":"Bitra","year":"2018","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.10.4897","article-title":"4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function","volume":"168","author":"Wen","year":"2002","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.2017106888","article-title":"4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses","volume":"215","author":"Menk","year":"2018","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.11.5483","article-title":"Immune responses in 4-1BB (CD137)-deficient mice","volume":"168","author":"Kwon","year":"2002","journal-title":"J Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/j.jaci.2019.03.002","article-title":"Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency","volume":"144","author":"Alosaimi","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000644","article-title":"CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis","volume":"134","author":"Somekh","year":"2019","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190678","article-title":"Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells","volume":"216","author":"Rodriguez","year":"2019","journal-title":"J Exp Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-03-208215","article-title":"Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma","volume":"114","author":"Middendorp","year":"2009","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxf080","article-title":"4-1BB co-stimulation enhances human CD8(+) T cell priming by augmenting the proliferation and survival of effector CD8(+) T cells","volume":"14","author":"Laderach","year":"2002","journal-title":"Int Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1111\/nyas.12937","article-title":"Primary immunodeficiencies and the control of Epstein-Barr virus infection","volume":"1356","author":"Palendira","year":"2015","journal-title":"Ann N Y Acad Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000928","article-title":"Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection","volume":"135","author":"Tangye","year":"2020","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.jaci.2011.11.013","article-title":"CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia","volume":"129","author":"van Montfrans","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1084\/jem.20160784","article-title":"Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection","volume":"214","author":"Izawa","year":"2017","journal-title":"J Exp Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1111\/j.1365-2567.2007.02653.x","article-title":"Role of endogenous 4-1BB in the development of systemic lupus erythematosus","volume":"122","author":"Vinay","year":"2007","journal-title":"Immunology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901619","article-title":"CD137 promotes proliferation and survival of human B cells","volume":"184","author":"Zhang","year":"2010","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1189\/jlb.72.1.35","article-title":"CD137 is expressed by follicular dendritic cells and costimulates B lymphocyte activation in germinal centers","volume":"72","author":"Pauly","year":"2002","journal-title":"J Leukoc Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nature10113","article-title":"Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia","volume":"475","author":"Puente","year":"2011","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-11-611194","article-title":"Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides","volume":"126","author":"McGirt","year":"2015","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of Malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.ccell.2018.03.018","article-title":"Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer","volume":"33","author":"Hellmann","year":"2018","journal-title":"Cancer Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev.immunol.23.021704.115839","article-title":"TNF\/TNFR family members in costimulation of T cell responses","volume":"23","author":"Watts","year":"2005","journal-title":"Annu Rev Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.9.4882","article-title":"4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1","volume":"169","author":"Lee","year":"2002","journal-title":"J\u00a0Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1016\/j.immuni.2023.06.007","article-title":"TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation","volume":"56","author":"Pichler","year":"2023","journal-title":"Immunity"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e69677","DOI":"10.1371\/journal.pone.0069677","article-title":"4-1BB signaling activates the t cell factor 1 effector\/\u03b2-catenin pathway with delayed kinetics via ERK signaling and delayed PI3K\/AKT activation to promote the proliferation of CD8+ T Cells","volume":"8","author":"Lee","year":"2013","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1733","article-title":"Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes","volume":"71","author":"Palaz\u00f3n","year":"2011","journal-title":"Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002681","article-title":"4-1BB triggering ameliorates experimental autoimmune encephalomyelitis by modulating the balance between Th17 and regulatory T cells","volume":"187","author":"Kim","year":"2011","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-1029","article-title":"CD137 (4-1BB)-based cancer immunotherapy on its 25th anniversary","volume":"13","author":"Melero","year":"2023","journal-title":"Cancer Discov"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2023.2167189","article-title":"The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy","volume":"15","author":"Claus","year":"2023","journal-title":"MAbs"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1605221\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T05:31:24Z","timestamp":1754458284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1605221\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2025.1605221"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1605221","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,6]]},"article-number":"1605221"}}