{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:16:35Z","timestamp":1790997395485,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["18K17037"],"award-info":[{"award-number":["18K17037"]}]},{"name":"Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology","award":["29-19"],"award-info":[{"award-number":["29-19"]}]},{"name":"Joint Usage and Joint Research Programs, the Institute of Advanced Medical Sciences, Tokushima University","award":["B-14"],"award-info":[{"award-number":["B-14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4+ T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sj\u00f6gren\u2019s syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis.<\/jats:p>","DOI":"10.3390\/ijms22052302","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T02:08:17Z","timestamp":1614305297000},"page":"2302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulation in Salivary Glands of Aged and Sj\u00f6gren\u2019s Syndrome Model Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Mie","family":"Kurosawa","sequence":"first","affiliation":[{"name":"Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Shikama","sequence":"additional","affiliation":[{"name":"Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masae","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rieko","family":"Arakaki","sequence":"additional","affiliation":[{"name":"Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naozumi","family":"Ishimaru","sequence":"additional","affiliation":[{"name":"Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Oral Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu 474-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1600-0528.1993.tb00744.x","article-title":"Subjective reports of oral dryness in an older adult population","volume":"21","author":"Locker","year":"1993","journal-title":"Community Dent. Oral Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1600-0528.1997.tb00928.x","article-title":"Prevalence of perceived symptoms of dry mouth in an adult Swedish population-relation to age, sex and pharmacotherapy","volume":"25","author":"Nederfors","year":"1997","journal-title":"Community Dent. Oral Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1875-595X.2000.tb00554.x","article-title":"Saliva in health and disease: An appraisal and update","volume":"50","author":"Sreebny","year":"2000","journal-title":"Int. Dent. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/0030-4220(88)90268-X","article-title":"Xerostomia. Part I: Relationship to other oral symptoms and salivary gland hypofunction","volume":"66","author":"Sreebny","year":"1988","journal-title":"Oral Surg. Oral Med. Oral Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0140-6736(05)66990-5","article-title":"Sj\u00f6gren\u2019s syndrome","volume":"366","author":"Fox","year":"2005","journal-title":"Lancet (Lond. Engl.)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"900","DOI":"10.2337\/diacare.15.7.900","article-title":"Xerostomia in diabetes mellitus","volume":"15","author":"Sreebny","year":"1992","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jaut.2012.01.004","article-title":"Sex steroids in Sj\u00f6gren\u2019s syndrome","volume":"39","author":"Konttinen","year":"2012","journal-title":"J. Autoimmun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/ageing\/13.3.159","article-title":"Age-related changes in structure of labial minor salivary glands","volume":"13","year":"1984","journal-title":"Age Ageing"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nrm2233","article-title":"Cellular senescence: When bad things happen to good cells","volume":"8","author":"Campisi","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1007\/s00018-012-0970-0","article-title":"Immune aging and autoimmunity","volume":"69","author":"Goronzy","year":"2012","journal-title":"Cell. Mol. Life Sci. Cmls"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nri3567","article-title":"Human memory T cells: Generation, compartmentalization and homeostasis","volume":"14","author":"Farber","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nri2318","article-title":"Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections","volume":"8","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15807","DOI":"10.1073\/pnas.0908805106","article-title":"PD-1+ memory phenotype CD4+ T cells expressing C\/EBPalpha underlie T cell immunodepression in senescence and leukemia","volume":"106","author":"Shimatani","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fimmu.2013.00131","article-title":"The janus head of T cell aging-Autoimmunity and immunodeficiency","volume":"4","author":"Goronzy","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4626","DOI":"10.1172\/JCI88606","article-title":"Obesity accelerates T cell senescence in murine visceral adipose tissue","volume":"126","author":"Shirakawa","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5725","DOI":"10.4049\/jimmunol.1500319","article-title":"A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production","volume":"194","author":"Tahir","year":"2015","journal-title":"J. Immunol. (Baltim. Md. 1950)"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1002\/art.23073","article-title":"Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sj\u00f6gren\u2019s syndrome: Correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development","volume":"56","author":"Manoussakis","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.3389\/fimmu.2018.02594","article-title":"CCL22-Producing Resident Macrophages Enhance T Cell Response in Sj\u00f6gren\u2019s Syndrome","volume":"9","author":"Ushio","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1002\/art.40230","article-title":"NF-\u03baB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sj\u00f6gren\u2019s Syndrome","volume":"69","author":"Kurosawa","year":"2017","journal-title":"Arthritis Rheumatol. (Hobokenn. J.)"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1111\/acel.12337","article-title":"Dysregulation of the Bmi-1\/p16(Ink\u2074a) pathway provokes an aging-associated decline of submandibular gland function","volume":"14","author":"Yamakoshi","year":"2015","journal-title":"Aging Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s10522-019-09797-3","article-title":"Submandibular gland-specific inflammaging-induced hyposalivation in the male senescence-accelerated mouse prone -1 line (SAM-P1)","volume":"20","author":"Miyagi","year":"2019","journal-title":"Biogerontology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jaut.2010.06.011","article-title":"The role of intrinsic epithelial activation in the pathogenesis of Sj\u00f6gren\u2019s syndrome","volume":"35","author":"Manoussakis","year":"2010","journal-title":"J. Autoimmun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.stemcr.2015.11.009","article-title":"Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals","volume":"6","author":"Maimets","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1172\/JCI22475","article-title":"Ink4a\/Arf expression is a biomarker of aging","volume":"114","author":"Krishnamurthy","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1474-9726.2009.00489.x","article-title":"Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging","volume":"8","author":"Liu","year":"2009","journal-title":"Aging Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9620","DOI":"10.1002\/anie.201603328","article-title":"Detection of LacZ-Positive Cells in Living Tissue with Single-Cell Resolution","volume":"55","author":"Doura","year":"2016","journal-title":"Angew. Chem. (Int. Ed. Engl.)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat. Reviews. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s41232-018-0082-9","article-title":"The impact of senescence-associated T cells on immunosenescence and age-related disorders","volume":"38","author":"Fukushima","year":"2018","journal-title":"Inflamm. Regen."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/intimm\/8.7.1067","article-title":"Defects of somatic hypermutation and class switching in alymphoplasia (aly) mutant mice","volume":"8","author":"Shinkura","year":"1996","journal-title":"Int. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.clim.2014.12.010","article-title":"The osteopontin transgenic mouse is a new model for Sj\u00f6gren\u2019s syndrome","volume":"157","author":"Kramer","year":"2015","journal-title":"Clin. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1084\/jem.20080174","article-title":"Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sj\u00f6gren\u2019s syndrome-like autoimmune exocrinopathy","volume":"205","author":"Ishimaru","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5893","DOI":"10.1172\/JCI136466","article-title":"DCAF1 regulates Treg senescence via the ROS axis during immunological aging","volume":"130","author":"Guo","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.it.2016.09.002","article-title":"Senescence of T Lymphocytes: Implications for Enhancing Human Immunity","volume":"37","author":"Akbar","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1189\/jlb.0506364","article-title":"Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb\/c mice","volume":"81","author":"Zhao","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.immuni.2016.01.009","article-title":"Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells","volume":"44","author":"Kuswanto","year":"2016","journal-title":"Immunity"},{"key":"ref_37","first-page":"2438","article-title":"T regulatory cells are markedly diminished in diseased salivary glands of patients with primary Sj\u00f6gren\u2019s syndrome","volume":"34","author":"Li","year":"2007","journal-title":"J. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.2353\/ajpath.2008.080246","article-title":"Foxp3+ T-regulatory cells in Sjogren\u2019s syndrome: Correlation with the grade of the autoimmune lesion and certain adverse prognostic factors","volume":"173","author":"Christodoulou","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1189\/jlb.0113036","article-title":"CXCL13 is elevated in Sj\u00f6gren\u2019s syndrome in mice and humans and is implicated in disease pathogenesis","volume":"94","author":"Kramer","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7970","DOI":"10.1038\/s41598-017-08631-5","article-title":"Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation","volume":"7","author":"Dragin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1073\/pnas.1818313116","article-title":"Cells exhibiting strong p16 (INK4a) promoter activation in vivo display features of senescence","volume":"116","author":"Liu","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jpor.2014.11.001","article-title":"Dry mouth: A critical topic for older adult patients","volume":"59","author":"Han","year":"2015","journal-title":"J. Prosthodont. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular Senescence: Defining a Path Forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1038\/s41467-020-16347-w","article-title":"The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice","volume":"11","author":"Yoshida","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100982","DOI":"10.1016\/j.arr.2019.100982","article-title":"Ageing, age-related diseases and oxidative stress: What to do next?","volume":"57","author":"Luo","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/35041687","article-title":"Oxidants, oxidative stress and the biology of ageing","volume":"408","author":"Finkel","year":"2000","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3164\/jcbn.16-79","article-title":"Relationship between hyposalivation and oxidative stress in aging mice","volume":"61","author":"Yamauchi","year":"2017","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3164\/jcbn.15-150","article-title":"Astaxanthin affects oxidative stress and hyposalivation in aging mice","volume":"59","author":"Kuraji","year":"2016","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1159\/000098211","article-title":"Possible involvement of oxidative stress in salivary gland of patients with Sjogren\u2019s syndrome","volume":"73","author":"Ryo","year":"2006","journal-title":"Pathobiol. J. Immunopathol. Mol. Cell. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3109\/10715762.2012.748904","article-title":"Sj\u00f8gren\u2019s syndrome-associated oxidative stress and mitochondrial dysfunction: Prospects for chemoprevention trials","volume":"47","author":"Pagano","year":"2013","journal-title":"Free Radic. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8329","DOI":"10.18632\/aging.102322","article-title":"Involvement of adiponectin in age-related increases in tear production in mice","volume":"11","author":"Shikama","year":"2019","journal-title":"Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.2337\/diabetes.50.9.2094","article-title":"PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein","volume":"50","author":"Maeda","year":"2001","journal-title":"Diabetes"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.3892\/mmr.2014.2041","article-title":"Decreased PPAR-\u03b3 expression in the conjunctiva and increased expression of TNF-\u03b1 and IL-1\u03b2 in the conjunctiva and tear fluid of dry eye mice","volume":"9","author":"Chen","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jaut.2017.09.007","article-title":"Impaired anti-inflammatory activity of PPAR\u03b3 in the salivary epithelia of Sj\u00f6gren\u2019s syndrome patients imposed by intrinsic NF-\u03baB activation","volume":"86","author":"Vakrakou","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_55","first-page":"4886","article-title":"Anti-inflammatory effect of peroxisome proliferator-activated receptor-\u03b3 (PPAR-\u03b3) on non-obese diabetic mice with Sjogren\u2019s syndrome","volume":"7","author":"Li","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1165\/rcmb.2014-0312MA","article-title":"Isolation of epithelial, endothelial, and immune cells from lungs of transgenic mice with oncogene-induced lung adenocarcinomas","volume":"52","author":"Bantikassegn","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_57","unstructured":"(2021). GraphPad InStat, GraphPad InStat Software Inc.. version 3.10."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2302\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:28:46Z","timestamp":1760160526000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":57,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22052302"],"URL":"https:\/\/doi.org\/10.3390\/ijms22052302","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,25]]}}}