{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:10:41Z","timestamp":1785431441957,"version":"3.56.0"},"reference-count":72,"publisher":"Rockefeller University Press","issue":"8","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"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":["DK107541"],"award-info":[{"award-number":["DK107541"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK121747"],"award-info":[{"award-number":["DK121747"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:p>CD137 is expressed in a subset of Foxp3+ regulatory CD4 T cells (Tregs), but its immunoregulatory role is not fully defined. Due to alternative splicing that removes the transmembrane domain\u2013encoding exon, CD137 exists in both membrane and soluble forms. We investigated the function of CD137 in Foxp3+ Tregs using the NOD mouse model of type 1 diabetes (T1D). Foxp3+ Treg\u2013specific deletion of CD137 reduced circulating soluble CD137 and accelerated T1D development, driven by heightened clonal expansion and differentiation of effector T cells in pancreatic islets. CD137 deficiency in Foxp3+ Tregs reduced their frequency in islets and impaired their differentiation toward a suppressive phenotype. Restoring soluble CD137 in Foxp3+ Tregs lacking its membrane form reduced islet T cell activation and mitigated T1D acceleration without altering the accumulation of suppressive Foxp3+ Tregs. Our results indicate that both soluble and membrane forms of CD137 expressed by Foxp3+ Tregs are critical for immunoregulation, and they independently restrain T1D development.<\/jats:p>","DOI":"10.1084\/jem.20252647","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T15:04:47Z","timestamp":1783436687000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Both soluble and cell surface CD137 expressed by Foxp3+ CD4 T cells restrain autoimmune diabetes"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7953-5785","authenticated-orcid":true,"given":"Rabia","family":"Nabi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 1 Department of Pediatrics, , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Max McGee Research Center for Juvenile Diabetes, Medical College of Wisconsin 2 , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4023-7339","authenticated-orcid":true,"given":"Chien-Wei","family":"Lin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Data Science Institute, Medical College of Wisconsin 3 Division of Biostatistics, , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-5679","authenticated-orcid":true,"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Data Science Institute, Medical College of Wisconsin 3 Division of Biostatistics, , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-0384","authenticated-orcid":true,"given":"Ashley E.","family":"Ciecko","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 1 Department of Pediatrics, , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Max McGee Research Center for Juvenile Diabetes, Medical College of Wisconsin 2 , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 4 Department of Microbiology and Immunology, , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8869-3697","authenticated-orcid":true,"given":"Bardees M.","family":"Foda","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 1 Department of Pediatrics, , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Max McGee Research Center for Juvenile Diabetes, Medical College of Wisconsin 2 , Milwaukee, WI,","place":["USA"]},{"name":"National Research Centre 5 Department of Molecular Genetics and Enzymology, , Dokki,","place":["Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1483-0184","authenticated-orcid":true,"given":"Yushu","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Data Science Institute, Medical College of Wisconsin 3 Division of Biostatistics, , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7958-1886","authenticated-orcid":true,"given":"Amber","family":"Drewek","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 1 Department of Pediatrics, , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Max McGee Research Center for Juvenile Diabetes, Medical College of Wisconsin 2 , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-7582","authenticated-orcid":true,"given":"Scott M.","family":"Lieberman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Carver College of Medicine, University of Iowa 6 Stead Family Department of Pediatrics, , Iowa City, IA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/036jqmy94","id-type":"ROR","asserted-by":"publisher"}],"name":"Interdisciplinary Graduate Program in Immunology, University of Iowa 7 , Iowa City, IA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9569-3932","authenticated-orcid":true,"given":"William M.","family":"Ridgway","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05rrcem69","id-type":"ROR","asserted-by":"publisher"}],"name":"Allergy and Clinical Immunology, University of California, Davis 8 Division of Rheumatology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9616-8841","authenticated-orcid":true,"given":"Yi-Guang","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 1 Department of Pediatrics, , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Max McGee Research Center for Juvenile Diabetes, Medical College of Wisconsin 2 , Milwaukee, WI,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00qqv6244","id-type":"ROR","asserted-by":"publisher"}],"name":"Medical College of Wisconsin 4 Department of Microbiology and Immunology, , Milwaukee, WI,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"2026070711031655700_bib1","doi-asserted-by":"publisher","first-page":"484","DOI":"10.4049\/jimmunol.1403039","article-title":"CD137 agonist therapy can reprogram regulatory T cells into cytotoxic CD4+ T cells with antitumor activity","volume":"196","author":"Akhmetzyanova","year":"2016","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib2","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1038\/icb.2017.38","article-title":"CD8 T cells contribute to lacrimal gland pathology in the nonobese diabetic mouse model of Sjogren syndrome","volume":"95","author":"Barr","year":"2017","journal-title":"Immunol. Cell Biol."},{"key":"2026070711031655700_bib3","doi-asserted-by":"publisher","first-page":"27","DOI":"10.3390\/antib13020027","article-title":"Factors governing B cell recognition of autoantigen and function in type 1 diabetes","volume":"13","author":"Bass","year":"2024","journal-title":"Antibodies (Basel)"},{"key":"2026070711031655700_bib4","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1016\/j.immuni.2018.09.014","article-title":"Antibodies to costimulatory receptor 4-1BB enhance anti-tumor immunity via T regulatory cell depletion and promotion of CD8 T cell effector function","volume":"49","author":"Buchan","year":"2018","journal-title":"Immunity"},{"key":"2026070711031655700_bib5","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41586-019-0969-x","article-title":"The single-cell transcriptional landscape of mammalian organogenesis","volume":"566","author":"Cao","year":"2019","journal-title":"Nature"},{"key":"2026070711031655700_bib6","doi-asserted-by":"publisher","first-page":"572","DOI":"10.4049\/jimmunol.1302100","article-title":"Effector-memory T cells develop in islets and report islet pathology in type 1 diabetes","volume":"192","author":"Chee","year":"2014","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib7","doi-asserted-by":"publisher","first-page":"68","DOI":"10.2337\/db13-0192","article-title":"Gene targeting in NOD mouse embryos using zinc-finger nucleases","volume":"63","author":"Chen","year":"2014","journal-title":"Diabetes"},{"key":"2026070711031655700_bib8","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1189\/jlb.1003491","article-title":"4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells","volume":"75","author":"Choi","year":"2004","journal-title":"J. Leukocyte Biol."},{"key":"2026070711031655700_bib9","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/cmi.2016.02","article-title":"4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation","volume":"14","author":"Choi","year":"2017","journal-title":"Cell Mol. Immunol."},{"key":"2026070711031655700_bib10","doi-asserted-by":"publisher","first-page":"113537","DOI":"10.1016\/j.isci.2025.113537","article-title":"An interleukin-27-centered cytokine circuit regulates macrophage and T cell interactions in autoimmune diabetes","volume":"28","author":"Ciecko","year":"2025","journal-title":"iScience"},{"key":"2026070711031655700_bib11","doi-asserted-by":"publisher","first-page":"935","DOI":"10.4049\/jimmunol.2200712","article-title":"Heterogeneity of islet-infiltrating IL-21+ CD4 T cells in a mouse model of type 1 diabetes","volume":"210","author":"Ciecko","year":"2023","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221920","article-title":"Single-cell profiling reveals unique features of diabetogenic T cells in anti-PD-1-induced type 1 diabetes mice","volume":"220","author":"Collier","year":"2023","journal-title":"J. Exp. Med."},{"key":"2026070711031655700_bib13","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.immuni.2023.01.004","article-title":"Principles of regulatory T cell function","volume":"56","author":"Dikiy","year":"2023","journal-title":"Immunity"},{"key":"2026070711031655700_bib14","doi-asserted-by":"publisher","first-page":"7295","DOI":"10.4049\/jimmunol.179.11.7295","article-title":"Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling","volume":"179","author":"Elpek","year":"2007","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib15","doi-asserted-by":"publisher","first-page":"2887","DOI":"10.4049\/jimmunol.1900485","article-title":"The CD137 ligand is important for Type 1 diabetes development but dispensable for the homeostasis of disease-suppressive CD137+ FOXP3+ regulatory CD4 T cells","volume":"204","author":"Foda","year":"2020","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib16","doi-asserted-by":"publisher","first-page":"3857","DOI":"10.4049\/jimmunol.1601851","article-title":"CD137 plays both pathogenic and protective roles in type 1 diabetes development in NOD mice","volume":"198","author":"Forsberg","year":"2017","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib17","doi-asserted-by":"publisher","first-page":"4316","DOI":"10.1038\/s41598-019-40898-8","article-title":"Combined congenic mapping and nuclease-based gene targeting for studying allele-specific effects of Tnfrsf9 within the Idd9.3 autoimmune diabetes locus","volume":"9","author":"Forsberg","year":"2019","journal-title":"Sci. Rep."},{"key":"2026070711031655700_bib18","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1172\/JCI128672","article-title":"A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target","volume":"130","author":"Freeman","year":"2020","journal-title":"J. Clin. Invest."},{"key":"2026070711031655700_bib19","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.celrep.2019.06.024","article-title":"Requirement of mitochondrial transcription factor A in tissue-resident regulatory T cell maintenance and function","volume":"28","author":"Fu","year":"2019","journal-title":"Cell Rep."},{"key":"2026070711031655700_bib20","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1038\/s41590-022-01338-4","article-title":"Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics","volume":"23","author":"Giles","year":"2022","journal-title":"Nat. Immunol."},{"key":"2026070711031655700_bib21","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1002\/eji.1830231037","article-title":"Molecular cloning of a ligand for the inducible T cell gene 4-1BB: A member of an emerging family of cytokines with homology to tumor necrosis factor","volume":"23","author":"Goodwin","year":"1993","journal-title":"Eur. J. Immunol."},{"key":"2026070711031655700_bib22","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1186\/s13059-019-1874-1","article-title":"Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression","volume":"20","author":"Hafemeister","year":"2019","journal-title":"Genome Biol."},{"key":"2026070711031655700_bib23","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1172\/JCI24219","article-title":"Developmental control of CD8 T cell-avidity maturation in autoimmune diabetes","volume":"115","author":"Han","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2026070711031655700_bib24","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1158\/2767-9764.CRC-23-0500","article-title":"IFNgamma production by functionally reprogrammed tregs promotes antitumor efficacy of OX40\/CD137 bispecific agonist therapy","volume":"4","author":"Imianowski","year":"2024","journal-title":"Cancer Res. Commun."},{"key":"2026070711031655700_bib25","doi-asserted-by":"publisher","first-page":"186","DOI":"10.2337\/db06-0793","article-title":"Modulating protective and pathogenic CD4+ subsets via CD137 in type 1 diabetes","volume":"56","author":"Irie","year":"2007","journal-title":"Diabetes"},{"key":"2026070711031655700_bib26","doi-asserted-by":"publisher","first-page":"2566","DOI":"10.3389\/fimmu.2019.02566","article-title":"Soluble CD137 ameliorates acute type 1 diabetes by inducing T cell anergy","volume":"10","author":"Itoh","year":"2019","journal-title":"Front. Immunol."},{"key":"2026070711031655700_bib27","doi-asserted-by":"publisher","first-page":"5001","DOI":"10.4049\/jimmunol.1101013","article-title":"The B10 Idd9.3 locus mediates accumulation of functionally superior CD137+ Regulatory T cells in the nonobese diabetic type 1 diabetes model","volume":"189","author":"Kachapati","year":"2012","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib28","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.jaut.2013.09.002","article-title":"Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice","volume":"47","author":"Kachapati","year":"2013","journal-title":"J. Autoimmun."},{"key":"2026070711031655700_bib29","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.bbmt.2011.09.004","article-title":"Host CD25+CD4+Foxp3+ regulatory T cells primed by anti-CD137 mAbs inhibit graft-versus-host disease","volume":"18","author":"Kim","year":"2012","journal-title":"Biol. Blood Marrow Transpl."},{"key":"2026070711031655700_bib30","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1073\/pnas.86.6.1963","article-title":"cDNA sequences of two inducible T-cell genes","volume":"86","author":"Kwon","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026070711031655700_bib31","doi-asserted-by":"publisher","first-page":"4882","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. Immunol."},{"key":"2026070711031655700_bib32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.ymthe.2024.12.010","article-title":"CD137-expressing regulatory T cells in cancer and autoimmune diseases","volume":"33","author":"Lee","year":"2025","journal-title":"Mol. Ther."},{"key":"2026070711031655700_bib33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1013543","article-title":"Single-cell analysis reveals an important role of CD137L+ macrophages in the host response to uropathogenic Escherichia coli infection in the bladder","volume":"21","author":"Liu","year":"2025","journal-title":"Plos Pathog."},{"key":"2026070711031655700_bib34","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1002\/eji.201948393","article-title":"Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-\u03baB","volume":"50","author":"Lubrano di Ricco","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"2026070711031655700_bib35","doi-asserted-by":"publisher","first-page":"353","DOI":"10.3390\/cells10020353","article-title":"Regulatory T cells inhibit T cell activity by downregulating CD137 ligand via CD137 trogocytosis","volume":"10","author":"Luu","year":"2021","journal-title":"Cells"},{"key":"2026070711031655700_bib36","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/s1074-7613(00)00012-1","article-title":"The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137","volume":"13","author":"Lyons","year":"2000","journal-title":"Immunity"},{"key":"2026070711031655700_bib37","doi-asserted-by":"publisher","first-page":"E10672","DOI":"10.1073\/pnas.1810580115","article-title":"Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types","volume":"115","author":"Magnuson","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026070711031655700_bib38","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/ni.2849","article-title":"Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells","volume":"15","author":"Mahmud","year":"2014","journal-title":"Nat. Immunol."},{"key":"2026070711031655700_bib39","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/nature05478","article-title":"Foxp3 occupancy and regulation of key target genes during T-cell stimulation","volume":"445","author":"Marson","year":"2007","journal-title":"Nature"},{"key":"2026070711031655700_bib40","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1084\/jem.20171068","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":"2026070711031655700_bib41","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1002\/(SICI)1521-4141(199801)28:01&lt;290::AID-IMMU290&gt;3.0.CO;2-S","article-title":"A soluble form of CD137 (ILA\/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis","volume":"28","author":"Michel","year":"1998","journal-title":"Eur. J. Immunol."},{"key":"2026070711031655700_bib42","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.immuni.2019.01.001","article-title":"Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation","volume":"50","author":"Miragaia","year":"2019","journal-title":"Immunity"},{"key":"2026070711031655700_bib43","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.immuni.2025.02.011","article-title":"The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation","volume":"58","author":"Neuwirth","year":"2025","journal-title":"Immunity"},{"key":"2026070711031655700_bib44","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1038\/s41590-021-00987-1","article-title":"TCF-1 controls Treg cell functions that regulate inflammation, CD8+ T cell cytotoxicity and severity of colon cancer","volume":"22","author":"Osman","year":"2021","journal-title":"Nat. Immunol."},{"key":"2026070711031655700_bib45","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1016\/j.cell.2017.05.005","article-title":"Interferon-\u03b3 Drives Treg fragility to promote anti-tumor immunity","volume":"169","author":"Overacre-Delgoffe","year":"2017","journal-title":"Cell"},{"key":"2026070711031655700_bib46","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.2174\/1381612821666150316120024","article-title":"Mouse models of primary sjogren\u2019s syndrome","volume":"21","author":"Park","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"2026070711031655700_bib47","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":"2026070711031655700_bib48","doi-asserted-by":"publisher","first-page":"918837","DOI":"10.3389\/fimmu.2022.918837","article-title":"The long and winding road: From mouse linkage studies to a novel human therapeutic pathway in type 1 diabetes","volume":"13","author":"Rojas","year":"2022","journal-title":"Front. Immunol."},{"key":"2026070711031655700_bib49","doi-asserted-by":"publisher","first-page":"103498","DOI":"10.1016\/j.jaut.2025.103498","article-title":"Alternate splicing converts human CD137 from costimulatory to immunosuppressive function","volume":"157","author":"Rojas","year":"2025","journal-title":"J. Autoimmun."},{"key":"2026070711031655700_bib50","doi-asserted-by":"publisher","first-page":"8093","DOI":"10.4049\/jimmunol.180.12.8093","article-title":"ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo","volume":"180","author":"Sabbagh","year":"2008","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib51","doi-asserted-by":"publisher","first-page":"1228486","DOI":"10.3389\/fimmu.2023.1228486","article-title":"Agonism of 4-1BB for immune therapy: A perspective on possibilities and complications","volume":"14","author":"Salek-Ardakani","year":"2023","journal-title":"Front. Immunol."},{"key":"2026070711031655700_bib52","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"2026070711031655700_bib53","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1038\/ni1565","article-title":"Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns","volume":"9","author":"Sebzda","year":"2008","journal-title":"Nat. Immunol."},{"key":"2026070711031655700_bib54","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1128\/jvi.79.2.1045-1052.2005","article-title":"Diabetes acceleration or prevention by a coxsackievirus B4 infection: Critical requirements for both interleukin-4 and gamma interferon","volume":"79","author":"Serreze","year":"2005","journal-title":"J. Virol."},{"key":"2026070711031655700_bib55","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/0378-1119(95)00349-b","article-title":"A mRNA variant encoding a soluble form of 4-1BB, a member of the murine NGF\/TNF receptor family","volume":"164","author":"Setareh","year":"1995","journal-title":"Gene"},{"key":"2026070711031655700_bib56","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1084\/jem.186.1.47","article-title":"4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses","volume":"186","author":"Shuford","year":"1997","journal-title":"J. Exp. Med."},{"key":"2026070711031655700_bib57","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.97322","article-title":"High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity","volume":"3","author":"Sprouse","year":"2018","journal-title":"JCI Insight"},{"key":"2026070711031655700_bib58","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2026070711031655700_bib59","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1182\/bloodadvances.2021006195","article-title":"4-1BBL-containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells","volume":"6","author":"Swatler","year":"2022","journal-title":"Blood Adv."},{"key":"2026070711031655700_bib60","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1158\/2326-6066.CIR-17-0767","article-title":"Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation","volume":"6","author":"Teijeira","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"2026070711031655700_bib61","doi-asserted-by":"publisher","first-page":"2906","DOI":"10.1016\/j.celrep.2017.08.068","article-title":"The TNF receptor superfamily-NF-\u03baB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues","volume":"20","author":"Vasanthakumar","year":"2017","journal-title":"Cell Rep."},{"key":"2026070711031655700_bib62","doi-asserted-by":"publisher","first-page":"1634","DOI":"10.4049\/jimmunol.1100077","article-title":"4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection","volume":"187","author":"Vezys","year":"2011","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib63","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/nri2343","article-title":"How regulatory T cells work","volume":"8","author":"Vignali","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2026070711031655700_bib64","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1146\/annurev-immunol-082423-040557","article-title":"TNF\/TNFR superfamily members in costimulation of T cell responses-revisited","volume":"43","author":"Watts","year":"2025","journal-title":"Annu. Rev. Immunol."},{"key":"2026070711031655700_bib65","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.4049\/jimmunol.176.3.1439","article-title":"Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo","volume":"176","author":"Willinger","year":"2006","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib66","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1038\/nature23665","article-title":"Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling","volume":"548","author":"Yang","year":"2017","journal-title":"Nature"},{"key":"2026070711031655700_bib67","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20192362","article-title":"Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes","volume":"217","author":"Zakharov","year":"2020","journal-title":"J. Exp. Med."},{"key":"2026070711031655700_bib68","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.immuni.2019.10.009","article-title":"CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer","volume":"51","author":"Zander","year":"2019","journal-title":"Immunity"},{"key":"2026070711031655700_bib69","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1111\/j.1365-3083.2007.01994.x","article-title":"Agonistic anti-4-1BB antibody promotes the expansion of natural regulatory T cells while maintaining Foxp3 expression","volume":"66","author":"Zhang","year":"2007","journal-title":"Scand. J. Immunol."},{"key":"2026070711031655700_bib70","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.4049\/jimmunol.173.4.2428","article-title":"The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells","volume":"173","author":"Zheng","year":"2004","journal-title":"J. Immunol."},{"key":"2026070711031655700_bib71","doi-asserted-by":"publisher","first-page":"abe6474","DOI":"10.1126\/science.abe6474","article-title":"Pan-cancer single-cell landscape of tumor-infiltrating T cells","volume":"374","author":"Zheng","year":"2021","journal-title":"Science"},{"key":"2026070711031655700_bib72","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1084\/jem.20080707","article-title":"Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity","volume":"205","author":"Zhou","year":"2008","journal-title":"J. Exp. Med."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20252647\/2037719\/jem_20252647.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20252647\/2037719\/jem_20252647.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T15:04:48Z","timestamp":1783436688000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/223\/8\/e20252647\/282801\/Both-soluble-and-cell-surface-CD137-expressed-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":72,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20252647","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]},"article-number":"e20252647"}}