{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:27:55Z","timestamp":1787113675250,"version":"build-2736575974"},"reference-count":24,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T00:00:00Z","timestamp":1786838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["DNW-19017"],"award-info":[{"award-number":["DNW-19017"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"award":["DNW-19017"],"award-info":[{"award-number":["DNW-19017"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hyogo Medical University","award":["Innovation Challenge Program 2025"],"award-info":[{"award-number":["Innovation Challenge Program 2025"]}]},{"award":["Innovation Challenge Program 2025"],"award-info":[{"award-number":["Innovation Challenge Program 2025"]}],"id":[{"id":"https:\/\/ror.org\/001yc7927","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Senescence-associated follicular helper T (SA-Tfh) cells contribute to tertiary lymphoid structure (TLS) formation in autoimmune diseases, yet the mechanisms guiding their localization to glandular niches remain unclear. In the Nishiura (NI) Sj\u00f6gren\u2019s disease (SjD) mouse model, we demonstrated that mouse SA-Tfh (mSA-Tfh; CD4+\/PD-1+\/CD153+) cells form TLSs specifically within the submandibular gland niche. We identified integrin \u03b17 (ITG\u03b17) expression in mSA-Tfh cells and examined its functional role. Adhesion of mSA-Tfh cells to laminin (LAM) \u03b12\/\u03b13\/\u03b14 was inhibited by anti-ITG\u03b17 IgG (E-2), and ITG\u03b17-deficient mSA-Tfh cells had reduced adhesion to LAM\u03b11\/\u03b12 compared with LAM\u03b13\/\u03b14\/\u03b15. Osteopontin production by mSA-Tfh cells, either alone or via interactions with mB220+\/PD-1+ cells, was suppressed by E-2, anti-LAM\u03b14 IgG, and ITG\u03b17 deficiency. In female NI mice, E-2 administration at 24 weeks reduced Greenspan grade 4 TLSs at 28 weeks by decreasing ITG\u03b17+\/CD153+ cell accumulation. mSA-Tfh infiltration into aged C57BL\/6 mice was similarly diminished by ITG\u03b17 or LAM\u03b14 deficiency. In human SjD cohorts, ITG\u03b17 expression positively correlated with CD153 expression (R2 = 0.41) in peripheral lymphocytes and with LAM\u03b14 expression (R2 = 0.35) in salivary gland vasculature and ducts. These findings suggest that circulating ITG\u03b17+ SA-Tfh cells adhere to the LAM\u03b14+ glandular niche to promote TLS formation in SjD.<\/jats:p>","DOI":"10.3390\/ijms27167307","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrin \u03b17-Driven Senescence-Associated Follicular Helper T Cell Adhesion Induces Tertiary Lymphoid Structures in Nishiura Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-0276","authenticated-orcid":false,"given":"Hiroshi","family":"Nishiura","sequence":"first","affiliation":[{"name":"Department of Genetics, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4773-1535","authenticated-orcid":false,"given":"Naoto","family":"Azuma","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Matsui","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teppei","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9859-7153","authenticated-orcid":false,"given":"Yoshiro","family":"Naito","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Medicine, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Imasaka","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Ohmuraya","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hyogo Medical University, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s41232-025-00393-2","article-title":"The roles of tertiary lymphoid structures in orchestrating immune responses in peripheral organs","volume":"45","author":"Taniguchi","year":"2025","journal-title":"Inflamm. Regen."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1016\/j.immuni.2023.08.009","article-title":"Tertiary lymphoid structures and B cells: An intratumoral immunity cycle","volume":"56","author":"Fridman","year":"2023","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1053\/j.gastro.2023.10.022","article-title":"Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13+CD103+CD8+ Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy","volume":"166","author":"Hu","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104260","DOI":"10.1016\/j.labinv.2025.104260","article-title":"Association Between CD4+\/Programmed Cell Death 1+\/CD153+ Cell Infiltration to the Aging Liver and Progression of Hepatic Steatosis in a Novel Metabolic Dysfunction-Associated Steatohepatitis Model Nishiura Mouse","volume":"106","author":"Suzuki","year":"2026","journal-title":"Lab. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112213","DOI":"10.1016\/j.mad.2026.112213","article-title":"Senescence-Associated Tertiary Lymphoid Structures in Sj\u00f6gren\u2019s Disease Model Nishiura Mice","volume":"232","author":"Nishiura","year":"2026","journal-title":"Mech. Ageing Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1093\/intimm\/dxy058","article-title":"Niches for hematopoietic stem cells and immune cell progenitors","volume":"31","author":"Sugiyama","year":"2019","journal-title":"Int. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00424-015-1743-z","article-title":"Hypoxia regulates the hematopoietic stem cell niche","volume":"468","author":"Morikawa","year":"2016","journal-title":"Pflug. Arch."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s12185-012-1071-4","article-title":"Roles of the hypoxia response system in hematopoietic and leukemic stem cells","volume":"95","author":"Takubo","year":"2012","journal-title":"Int. J. Hematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102323","DOI":"10.1016\/j.jbc.2022.102323","article-title":"Dynamics of integrin \u03b15\u03b21, fibronectin, and their complex reveal sites of interaction and conformational change","volume":"298","author":"Su","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"38174","DOI":"10.1074\/jbc.M210472200","article-title":"Alpha4beta1 integrin affinity changes govern cell adhesion","volume":"278","author":"Chigaev","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/emboj\/18.4.882","article-title":"Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2","volume":"18","author":"Soldi","year":"1999","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.scr.2016.02.043","article-title":"Embryonic stem cell-derived neural progenitors transplanted to the hippocampus migrate on host vasculature","volume":"16","author":"Lassiter","year":"2016","journal-title":"Stem Cell Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaal4165","DOI":"10.1126\/scisignal.aal4165","article-title":"Niche-derived laminin-511 promotes midbrain dopaminergic neuron survival and differentiation through YAP","volume":"10","author":"Zhang","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"102008","DOI":"10.1016\/j.matbio.2026.102008","article-title":"Basement membrane components define the microenvironment of aggregated fibroblasts in the skin and support their aggregation in vitro","volume":"146","author":"Machida","year":"2026","journal-title":"Matrix Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110419","DOI":"10.1016\/j.jbc.2025.110419","article-title":"Loss of integrin alpha7-mediated signaling induces a dendritic cell-like phenotype in macrophages cultured on laminin-211\/221 isoforms","volume":"301","author":"Yoshiba","year":"2025","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1006\/excr.2000.4806","article-title":"The role of extracellular and cytoplasmic splice domains of alpha7-integrin in cell adhesion and migration on laminins","volume":"255","author":"Mielenz","year":"2000","journal-title":"Exp. Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27651","DOI":"10.1074\/jbc.274.39.27651","article-title":"Activation of c-Raf-1 kinase signal transduction pathway in alpha(7) integrin-deficient mice","volume":"274","author":"Saher","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e146071","DOI":"10.1172\/JCI146071","article-title":"CD153\/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury","volume":"132","author":"Sato","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s12016-025-09021-w","article-title":"Age-Associated B Cells in Autoimmune Diseases: Pathogenesis and Clinical Implications","volume":"68","author":"Xie","year":"2025","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Takano, T., Kotaki, R., Park, J., Yoshida, T., Wakatsuki, Y., Tanokura, M., Miyakawa, T., Takahashi, K., Nakajima-Adachi, H., and Hachimura, S. (2020). Age-Dependent Decrease in the Induction of Regulatory T Cells Is Associated with Decreased Expression of RALDH2 in Mesenteric Lymph Node Dendritic Cells. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01555"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e156994","DOI":"10.1172\/JCI156994","article-title":"Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin \u03b14","volume":"132","author":"Li","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0002-9440(10)65584-8","article-title":"Endothelial cell integrin laminin receptor expression in multiple sclerosis lesions","volume":"153","author":"Sobel","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1046\/j.1365-2567.2002.01384.x","article-title":"Developmentally regulated interactions of human thymocytes with different laminin isoforms","volume":"105","author":"Kutlesa","year":"2002","journal-title":"Immunology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1093\/bioinformatics\/btu743","article-title":"CRISPRdirect: Software for designing CRISPR\/Cas guide RNA with reduced off-target sites","volume":"31","author":"Naito","year":"2015","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:17:36Z","timestamp":1787113056000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,16]]},"references-count":24,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167307"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167307","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,16]]}}}