{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:05:40Z","timestamp":1793642740727,"version":"4.5.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006315","name":"ReumaNederland","doi-asserted-by":"publisher","award":["17-2-403"],"award-info":[{"award-number":["17-2-403"]}],"id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Increased CCL5 expression and CD8 T cells have been shown to be pivotal regulators of immunopathology in primary Sj\u00f6gren\u2019s syndrome (pSS) and pSS-like disease. Increased CCL5 expression by CCR9+ CD4 T cells has previously been implicated as a contributor to immunopathology in pSS. The role of CD8 T cells and in particular CCR9+ CD8 T cells and their potential to secrete CCL5 has not previously been studied in pSS. In this study we investigated both CCR9 and CCL5 expression by CD8 T cells in pSS patients compared to healthy controls (HC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CCR9 expression on CD8 T cells from peripheral blood was compared between patients with pSS and HC by flow cytometry. Intracellular CCL5 expression by naive, memory and effector CCR9- and CCR9+ CD8 T cells was assessed. In addition, the capacity and pace of CCL5 release upon T cell activation was determined for all subsets and compared with CD4 T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The frequency of circulating CCR9+ CD8 T cells in pSS patients is increased compared to HC. Antigen-experienced CD8 T cells, especially CCR9+ effector CD8 T cells, express the highest CCL5 levels, and release the highest levels of CCL5 upon activation. Memory and effector CD8 T cells of pSS patients express significantly less CCL5 and subsequently release less CCL5 upon stimulation compared to HC. CCR9+ CD8 T cells rapidly release CCL5 and significantly more than CCR9+ CD4 T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CCR9+ CD8 T cells express more CCL5 than CCR9- CD8 T cells. CCL5 is rapidly released upon activation, resulting in reduced intracellular expression. Reduced CCL5 expression by an elevated number of antigen-experienced CCR9-expressing CD8 T cells in pSS patients points towards increased release<jats:italic>in vivo<\/jats:italic>. This suggests that CCL5 release by CCR9+ CD8 T cells contributes to immunopathology in pSS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.887972","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T10:27:53Z","timestamp":1654079273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["CCL5 Release by CCR9+ CD8 T Cells: A Potential Contributor to Immunopathology of Primary Sj\u00f6gren\u2019s Syndrome"],"prefix":"10.3389","volume":"13","author":[{"given":"Anneline C.","family":"Hinrichs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie L. M.","family":"Blokland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aike A.","family":"Kruize","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris P. J.","family":"Lafeber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen L.","family":"Leavis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel A. G.","family":"van Roon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)66990-5","article-title":"Sjogren\u2019s Syndrome","volume":"366","author":"Fox","year":"2005","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16047","DOI":"10.1038\/nrdp.2016.47","article-title":"Sjogren Syndrome","volume":"2","author":"Brito-Zer\u00f3n","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.rdc.2016.03.006","article-title":"Salivary Gland Pathology in Sjogren\u2019s Syndrome","volume":"42","author":"Campos","year":"2016","journal-title":"Rheum Dis Clin North Am"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/art.40676","article-title":"Tissue-Resident Memory CD8+ T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sj\u00f6gren\u2019s Syndrome","volume":"71","author":"Gao","year":"2019","journal-title":"Arthritis Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005727","article-title":"Sj\u00f6gren\u2019s Syndrome: NCR3\/NKp30 Contributes to Pathogenesis in Primary Sj\u00f6gren\u2019s Syndrome","volume":"5","author":"Rusakiewicz","year":"2013","journal-title":"Sci Trans Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.706737","article-title":"NKp30 Receptor Upregulation in Salivary Glands of Sj\u00f6gren\u2019s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment","volume":"12","author":"Pontarini","year":"2021","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-203187","article-title":"Potential Involvement of the IL-33\u2013ST2 Axis in the Pathogenesis of Primary Sj\u00f6gren\u2019s Syndrome","volume":"73","author":"Awada","year":"2014","journal-title":"Ann Rheum Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2014.891439","article-title":"B-Cell Hyperactivity in Primary Sjogren\u2019s Syndrome","volume":"10","author":"Kroese","year":"2014","journal-title":"Expert Rev Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.04.133","article-title":"Role of the Frequency of Blood CD4(+) CXCR5(+) CCR6(+) T Cells in Autoimmunity in Patients With Sjogren\u2019s Syndrome","volume":"422","author":"Li","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"B10","article-title":"CD4+CXCR5+ Follicular Helper T Cells in Salivary Gland Promote B Cells Maturation in Patients With Primary Sjogren\u2019s Syndrome","volume":"7","author":"Jin","year":"2014","journal-title":"Int J Clin Exp Pathol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.jaut.2013.11.003","article-title":"Differentiation of Follicular Helper T Cells by Salivary Gland Epithelial Cells in Primary Sjogren\u2019s Syndrome","volume":"51","author":"Gong","year":"2014","journal-title":"J Autoimmun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.clim.2013.02.024","article-title":"Follicular Helper T Cells may Play an Important Role in the Severity of Primary Sjogren\u2019s Syndrome","volume":"147","author":"Szabo","year":"2013","journal-title":"Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217646","article-title":"Unique Expansion of IL-21+ Tfh and Tph Cells Under Control of ICOS Identifies Sj\u00f6gren\u2019s Syndrome With Ectopic Germinal Centres and MALT Lymphoma","volume":"79","author":"Pontarini","year":"2020","journal-title":"Ann Rheum Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.01.021","article-title":"A Subset of Interleukin-21+ Chemokine Receptor CCR9+ T Helper Cells Target Accessory Organs of the Digestive System in Autoimmunity","volume":"34","author":"McGuire","year":"2011","journal-title":"Immunity"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/art.40182","article-title":"Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sj\u00f6gren\u2019s Syndrome: Potential New Axis in Lymphoid Neogenesis","volume":"69","author":"Blokland","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.5.761","article-title":"Lymphocyte CC Chemokine Receptor 9 and Epithelial Thymus-Expressed Chemokine (TECK) Expression Distinguish the Small Intestinal Immune Compartment: Epithelial Expression of Tissue-Specific Chemokines as an Organizing Principle in Regional Immunity","volume":"192","author":"Kunkel","year":"2000","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.702733","article-title":"Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sj\u00f6gren\u2019s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule","volume":"12","author":"Hinrichs","year":"2021","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200319607","article-title":"Expression of the Alpha1beta1 Integrin, VLA-1, Marks a Distinct Subset of Human CD4+ Memory T Cells","volume":"112","author":"Goldstein","year":"2003","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/34814","article-title":"CCR5 is Characteristic of Th1 Lymphocytes","volume":"391","author":"Loetscher","year":"1998","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02096","article-title":"Plasmacytoid DCs From Patients With Sj\u00f6gren\u2019s Syndrome Are Transcriptionally Primed for Enhanced Pro-Inflammatory Cytokine Production","volume":"10","author":"Hillen","year":"2019","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/37.7.779","article-title":"Chemokine Expression and Leucocyte Infiltration in Sjogren\u2019s Syndrome","volume":"37","author":"Cuello","year":"1998","journal-title":"Br J Rheumatol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/j.1365-2249.2012.04587.x","article-title":"Cytokine\/chemokine Profiles Contribute to Understanding the Pathogenesis and Diagnosis of Primary Sj\u00f6gren\u2019s Syndrome","volume":"169","author":"Moriyama","year":"2012","journal-title":"Clin Exp Immunol"},{"key":"B23","article-title":"T Cell Attractant Chemokine Expression Initiates Lacrimal Gland Destruction in Nonobese Diabetic Mice","volume":"79","author":"T\u00f6rnwall","year":"1999","journal-title":"Lab Invest"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(04)00027-5","article-title":"Human CD8 T Cells Store RANTES in a Unique Secretory Compartment and Release It Rapidly After TcR Stimulation","volume":"20","author":"Catalfamo","year":"2004","journal-title":"Immunity"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/36129","article-title":"\u03b2-Chemokines are Released From HIV-1-Specific Cytolytic T-Cell Granules Complexed to Proteoglycans","volume":"391","author":"Wagner","year":"1998","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"109902","DOI":"10.1016\/j.celrep.2021.109902","article-title":"Arthritis Flares Mediated by Tissue-Resident Memory T Cells in the Joint","volume":"37","author":"Chang","year":"2021","journal-title":"Cell Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018017244","article-title":"CXCR5 and ICOS Expression Identifies a CD8 T-Cell Subset With T FH Features in Hodgkin Lymphomas Key Points","volume":"2","author":"Le","year":"2018","journal-title":"Blood Adv"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210788","article-title":"Multiomic Disease Signatures Converge to Cytotoxic CD8 T Cells in Primary Sj\u00f6gren\u2019s Syndrome","volume":"76","author":"Tasaki","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1016\/j.jaci.2016.01.024","article-title":"Cytometry by Time-of-Flight Immunophenotyping Identifies a Blood Sjogren\u2019s Signature Correlating With Disease Activity and Glandular Inflammation","volume":"137","author":"Mingueneau","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kez268","article-title":"Epigenetically Quantified Immune Cells in Salivary Glands of Sj\u00f6gren\u2019s Syndrome Patients: A Novel Tool That Detects Robust Correlations of T Follicular Helper Cells With Immunopathology","volume":"59","author":"Blokland","year":"2020","journal-title":"Rheumatology"},{"key":"B31","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1002\/art.39859","article-title":"2016 American College of Rheumatology\/European League Against Rheumatism Classification Criteria for Primary Sjogren\u2019s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts","volume":"69","author":"Shiboski","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan3508","article-title":"Epigenetic Immune Cell Counting in Human Blood Samples for Immunodiagnostics","volume":"10","author":"Baron","year":"2018","journal-title":"Sci Trans Med"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.163.4.2226","article-title":"Preferential Localization of CD8+ Alpha E Beta 7+ T Cells Around Acinar Epithelial Cells With Apoptosis in Patients With Sj\u00f6gren\u2019s Syndrome","volume":"163","author":"Fujihara","year":"1999","journal-title":"J Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0723-4","article-title":"Tissue-Resident Memory CD8+ T Cells Shape Local and Systemic Secondary T Cell Responses","volume":"21","author":"Behr","year":"2020","journal-title":"Nat Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0607-7","article-title":"Developmental Plasticity Allows Outside-in Immune Responses by Resident Memory T Cells","volume":"21","author":"Fonseca","year":"2020","journal-title":"Nat Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830250319","article-title":"CD8+ and CD45RA+ Human Peripheral Blood Lymphocytes are Potent Sources of Macrophage Inflammatory Protein 1\u03b1, Interleukin-8 and RANTES","volume":"25","author":"Conlon","year":"1995","journal-title":"Eur J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1177\/039463201402700205","article-title":"Increased Expression of CCL4\/MIP-1P in CD8+ Cells and CD4+ Cells in Sarcoidosis","volume":"27","author":"Barczyk","year":"2014","journal-title":"Int J Immunopathol Pharmacol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/ar1913","article-title":"Expression of the Inflammatory Chemokines CCL5, CCL3 and CXCL10 in Juvenile Idiopathic Arthritis, and Demonstration of CCL5 Production by an Atypical Subset of CD8+ T Cells","volume":"8","author":"Pharoah","year":"2006","journal-title":"Arthritis Res Ther"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/art.38982","article-title":"The Efficacy of Abatacept in Reducing Synovial T Cell Activation by CD1c Myeloid Dendritic Cells is Overruled by the Stimulatory Effects of T Cell-Activating Cytokines","volume":"67","author":"Moret","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.0300-9475.2004.01432.x","article-title":"Circulating Cytokines in Primary Sj\u00f6gren\u2019s Syndrome Determined by a Multiplex Cytokine Array System","volume":"59","author":"Szodoray","year":"2004","journal-title":"Scand J Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.09.003","article-title":"Novel Autoantibodies in Sj\u00f6gren\u2019s Syndrome: A Comprehensive Review","volume":"18","author":"Mart\u00edn-Nares","year":"2019","journal-title":"Autoimmun Rev"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s40744-021-00334-8","article-title":"Sj\u00f6gren\u2019s Syndrome and Viral Infections","volume":"8","author":"Liu","year":"2021","journal-title":"Rheumatol Ther"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2014.892417","article-title":"EBV and Other Viruses as Triggers of Tertiary Lymphoid Structures in Primary Sj\u00f6gren\u2019s Syndrome","volume":"10","author":"Lucchesi","year":"2014","journal-title":"Expert Rev Clin Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.587380","article-title":"Epstein-Barr Virus and Systemic Autoimmune Diseases","volume":"11","author":"Houen","year":"2021","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jaut.2015.07.002","article-title":"Type I and II Interferon Signatures in Sjogren\u2019s Syndrome Pathogenesis: Contributions in Distinct Clinical Phenotypes and Sjogren\u2019s Related Lymphomagenesis","volume":"63","author":"Nezos","year":"2015","journal-title":"J Autoimmun"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/S41467-021-23472-7","article-title":"A New Molecular Classification to Drive Precision Treatment Strategies in Primary Sj\u00f6gren\u2019s Syndrome","volume":"12","author":"Soret","year":"2021","journal-title":"Nat Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.887972\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T22:56:34Z","timestamp":1675724194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.887972\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2022.887972"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.887972","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,1]]},"article-number":"887972"}}