{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T19:11:33Z","timestamp":1794251493426,"version":"4.9.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of &gt;16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8\n                    <jats:sup>+<\/jats:sup>\n                    subset expressing cytotoxic markers\/genes, and a Th17-like\n                    <jats:italic>RORC<\/jats:italic>\n                    + Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12\/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.\n                  <\/jats:p>","DOI":"10.1038\/s42003-021-02931-3","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T06:03:55Z","timestamp":1639461835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0241-5387","authenticated-orcid":false,"given":"Davide","family":"Simone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9163-8576","authenticated-orcid":false,"given":"Frank","family":"Penkava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ridley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4569-8513","authenticated-orcid":false,"given":"Stephen","family":"Sansom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2312-3754","authenticated-orcid":false,"given":"M. Hussein","family":"Al-Mossawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4597-0484","authenticated-orcid":false,"given":"Paul","family":"Bowness","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"2931_CR1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042718-041717","author":"S Sakaguchi","year":"2020","unstructured":"Sakaguchi, S. et al. Regulatory T cells and human disease. Annu. Rev. Immunol. https:\/\/doi.org\/10.1146\/annurev-immunol-042718-041717 (2020).","journal-title":"Annu. Rev. Immunol."},{"key":"2931_CR2","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1146\/annurev-immunol-032712-095948","volume":"34","author":"M Panduro","year":"2016","unstructured":"Panduro, M., Benoist, C. & Mathis, D. Tissue Tregs. Annu. Rev. Immunol. 34, 609\u2013633 (2016).","journal-title":"Annu. Rev. Immunol."},{"key":"2931_CR3","doi-asserted-by":"crossref","unstructured":"DiSpirito, J. R. et al. Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci. Immunol. 3, eaat5861 (2018).","DOI":"10.1126\/sciimmunol.aat5861"},{"key":"2931_CR4","doi-asserted-by":"crossref","first-page":"vi4","DOI":"10.1093\/rheumatology\/key001","volume":"57","author":"D Simone","year":"2018","unstructured":"Simone, D., Al Mossawi, M. H. & Bowness, P. Progress in our understanding of the pathogenesis of ankylosing spondylitis. Rheumatology (Oxf.) 57, vi4\u2013vi9 (2018).","journal-title":"Rheumatology (Oxf.)"},{"key":"2931_CR5","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/art.38291","volume":"66","author":"JA Smith","year":"2014","unstructured":"Smith, J. A. & Colbert, R. A. Review: the interleukin-23\/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond: IL-23\/IL-17 axis in SpA. Arthritis Rheumatol. 66, 231\u2013241 (2014).","journal-title":"Arthritis Rheumatol."},{"key":"2931_CR6","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/nature10434","volume":"478","author":"SK Lathrop","year":"2011","unstructured":"Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250\u2013254 (2011).","journal-title":"Nature"},{"key":"2931_CR7","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/nature12079","volume":"497","author":"A Cebula","year":"2013","unstructured":"Cebula, A. et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497, 258\u2013262 (2013).","journal-title":"Nature"},{"key":"2931_CR8","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.4049\/jimmunol.168.4.1644","volume":"168","author":"P Romagnoli","year":"2002","unstructured":"Romagnoli, P., Hudrisier, D. & van Meerwijk, J. P. M. Preferential recognition of self antigens despite normal thymic deletion of CD4(+)CD25(+) regulatory T cells. J. Immunol. 168, 1644\u20131648 (2002).","journal-title":"J. Immunol."},{"key":"2931_CR9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41590-018-0051-0","volume":"19","author":"D Zemmour","year":"2018","unstructured":"Zemmour, D. et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat. Immunol. 19, 291\u2013301 (2018).","journal-title":"Nat. Immunol."},{"key":"2931_CR10","first-page":"8187","volume":"15","author":"Y Yu","year":"2018","unstructured":"Yu, Y. et al. Recent advances in CD8+ regulatory T cell research. Oncol. Lett. 15, 8187\u20138194 (2018).","journal-title":"Oncol. Lett."},{"key":"2931_CR11","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1158\/0008-5472.CAN-11-1620","volume":"72","author":"S-R Woo","year":"2012","unstructured":"Woo, S.-R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape. Cancer Res. 72, 917\u2013927 (2012).","journal-title":"Cancer Res."},{"key":"2931_CR12","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.celrep.2014.09.045","volume":"9","author":"JR Fergusson","year":"2014","unstructured":"Fergusson, J. R. et al. CD161 defines a transcriptional and functional phenotype across distinct human T cell lineages. Cell Rep. 9, 1075\u20131088 (2014).","journal-title":"Cell Rep."},{"key":"2931_CR13","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/ng.2667","volume":"45","author":"International Genetics of Ankylosing Spondylitis Consortium (IGAS) et al.","year":"2013","unstructured":"International Genetics of Ankylosing Spondylitis Consortium (IGAS) et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730\u2013738 (2013).","journal-title":"Nat. Genet."},{"key":"2931_CR14","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1126\/science.aac4263","volume":"349","author":"C Ohnmacht","year":"2015","unstructured":"Ohnmacht, C. et al. The microbiota regulates type 2 immunity through ROR t+ T cells. Science 349, 989\u2013993 (2015).","journal-title":"Science"},{"key":"2931_CR15","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-18513-6","volume":"11","author":"F Penkava","year":"2020","unstructured":"Penkava, F. et al. Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis. Nat. Commun. 11, 4767 (2020).","journal-title":"Nat. Commun."},{"key":"2931_CR16","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/ni1240","volume":"6","author":"SK Bromley","year":"2005","unstructured":"Bromley, S. K., Thomas, S. Y. & Luster, A. D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat. Immunol. 6, 895\u2013901 (2005).","journal-title":"Nat. Immunol."},{"key":"2931_CR17","doi-asserted-by":"crossref","first-page":"8391","DOI":"10.4049\/jimmunol.181.12.8391","volume":"181","author":"T Yamazaki","year":"2008","unstructured":"Yamazaki, T. et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J. Immunol. 181, 8391\u20138401 (2008).","journal-title":"J. Immunol."},{"key":"2931_CR18","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1126\/science.aaa9420","volume":"349","author":"E Sefik","year":"2015","unstructured":"Sefik, E. et al. Mucosal immunology. Individual intestinal symbionts induce a distinct population of ROR\u03b3+ regulatory T cells. Science 349, 993\u2013997 (2015).","journal-title":"Science"},{"key":"2931_CR19","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/s41590-020-0602-z","volume":"21","author":"KR James","year":"2020","unstructured":"James, K. R. et al. Distinct microbial and immune niches of the human colon. Nat. Immunol. 21, 343\u2013353 (2020).","journal-title":"Nat. Immunol."},{"key":"2931_CR20","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41584-020-0454-9","volume":"16","author":"E Gracey","year":"2020","unstructured":"Gracey, E. et al. Revisiting the gut\u2013joint axis: links between gut inflammation and spondyloarthritis. Nat. Rev. Rheumatol. 16, 415\u2013433 (2020).","journal-title":"Nat. Rev. Rheumatol."},{"key":"2931_CR21","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1126\/science.1172702","volume":"326","author":"A Chaudhry","year":"2009","unstructured":"Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986\u2013991 (2009).","journal-title":"Science"},{"key":"2931_CR22","doi-asserted-by":"crossref","first-page":"101.7","DOI":"10.4049\/jimmunol.200.Supp.101.7","volume":"200","author":"YR Thaker","year":"2018","unstructured":"Thaker, Y. R., Andrews, L. P., Workman, C. J., Vignali, D. A. A. & Sharpe, A. H. Treg-specific LAG3 deletion reveals a key role for LAG3 in regulatory T cells to inhibit CNS autoimmunity. J. Immunol. 200, 101.7\u2013101.7 (2018).","journal-title":"J. Immunol."},{"key":"2931_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/nature25500","author":"M Xu","year":"2018","unstructured":"Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature https:\/\/doi.org\/10.1038\/nature25500 (2018).","journal-title":"Nature"},{"key":"2931_CR24","volume":"8","author":"MH Al-Mossawi","year":"2017","unstructured":"Al-Mossawi, M. H. et al. Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nat. Commun. 8, 1510 (2017).","journal-title":"Nat. Commun."},{"key":"2931_CR25","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1182\/blood-2012-08-443473","volume":"121","author":"AM Pesenacker","year":"2013","unstructured":"Pesenacker, A. M. et al. CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. Blood 121, 2647\u20132658 (2013).","journal-title":"Blood"},{"key":"2931_CR26","doi-asserted-by":"crossref","unstructured":"Duurland, C. L., Brown, C. C., O\u2019Shaughnessy, R. F. L. & Wedderburn, L. R. CD161+ Tconv and CD161+ Treg share a transcriptional and functional phenotype despite limited overlap in TCR\u03b2 repertoire. Front. Immunol. 8, 103 (2017).","DOI":"10.3389\/fimmu.2017.00103"},{"key":"2931_CR27","doi-asserted-by":"publisher","unstructured":"Povoleri, G. A. M. et al. Human retinoic acid\u2013regulated CD161 + regulatory T cells support wound repair in intestinal mucosa. Nat. Immunol. 1, https:\/\/doi.org\/10.1038\/s41590-018-0230-z (2018).","DOI":"10.1038\/s41590-018-0230-z"},{"key":"2931_CR28","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.humimm.2008.07.016","volume":"69","author":"E Billerbeck","year":"2008","unstructured":"Billerbeck, E. & Thimme, R. CD8+ regulatory T cells in persistent human viral infections. Hum. Immunol. 69, 771\u2013775 (2008).","journal-title":"Hum. Immunol."},{"key":"2931_CR29","doi-asserted-by":"crossref","first-page":"8029","DOI":"10.1073\/pnas.0702257104","volume":"104","author":"SA Joosten","year":"2007","unstructured":"Joosten, S. A. et al. Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. PNAS 104, 8029\u20138034 (2007).","journal-title":"PNAS"},{"key":"2931_CR30","doi-asserted-by":"crossref","unstructured":"Patterson, S. J. et al. T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression. J. Clin. Invest. 126, 1039\u20131051 (2016).","DOI":"10.1172\/JCI83987"},{"key":"2931_CR31","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.immuni.2004.09.002","volume":"21","author":"WJ Grossman","year":"2004","unstructured":"Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589\u2013601 (2004).","journal-title":"Immunity"},{"key":"2931_CR32","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/art.41129","volume":"72","author":"E Gracey","year":"2020","unstructured":"Gracey, E. et al. Altered cytotoxicity profile of CD8+ T cells in ankylosing spondylitis. Arthritis Rheumatol. 72, 428\u2013434 (2020).","journal-title":"Arthritis Rheumatol."},{"key":"2931_CR33","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.4049\/jimmunol.1900940","volume":"204","author":"JP Hewitson","year":"2020","unstructured":"Hewitson, J. P. et al. Malat1 suppresses immunity to infection through promoting expression of Maf and IL-10 in Th cells. J. Immunol. 204, 2949\u20132960 (2020).","journal-title":"J. Immunol."},{"key":"2931_CR34","doi-asserted-by":"crossref","first-page":"18226","DOI":"10.1074\/jbc.RA120.013023","volume":"295","author":"DL Morris","year":"2020","unstructured":"Morris, D. L., Johnson, S., Bleck, C. K. E., Lee, D.-Y. & Tjandra, N. Humanin selectively prevents the activation of pro-apoptotic protein BID by sequestering it into fibers. J. Biol. Chem. 295, 18226\u201318238 (2020).","journal-title":"J. Biol. Chem."},{"key":"2931_CR35","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/jnc.14258","volume":"144","author":"S Kusakari","year":"2018","unstructured":"Kusakari, S., Nawa, M., Sudo, K. & Matsuoka, M. Calmodulin-like skin protein protects against spatial learning impairment in a mouse model of Alzheimer disease. J. Neurochem. 144, 218\u2013233 (2018).","journal-title":"J. Neurochem."},{"key":"2931_CR36","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nri2470","volume":"9","author":"M Perretti","year":"2009","unstructured":"Perretti, M. & D\u2019Acquisto, F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat. Rev. Immunol. 9, 62\u201370 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"2931_CR37","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1016\/j.celrep.2017.08.068","volume":"20","author":"A Vasanthakumar","year":"2017","unstructured":"Vasanthakumar, A. et al. The TNF receptor superfamily-NF-\u03baB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues. Cell Rep. 20, 2906\u20132920 (2017).","journal-title":"Cell Rep."},{"key":"2931_CR38","doi-asserted-by":"crossref","first-page":"21666","DOI":"10.1073\/pnas.1909687116","volume":"116","author":"W-Y Tseng","year":"2019","unstructured":"Tseng, W.-Y. et al. TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells. PNAS 116, 21666\u201321672 (2019).","journal-title":"PNAS"},{"key":"2931_CR39","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.immuni.2019.01.001","volume":"50","author":"RJ Miragaia","year":"2019","unstructured":"Miragaia, R. J. et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 50, 493\u2013504.e7 (2019).","journal-title":"Immunity"},{"key":"2931_CR40","doi-asserted-by":"crossref","unstructured":"L\u00f6nnberg, T. et al. Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves TH1\/TFH fate bifurcation in malaria. Sci. Immunol. 2, eaal2192 (2017).","DOI":"10.1126\/sciimmunol.aal2192"},{"key":"2931_CR41","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.immuni.2016.10.032","volume":"45","author":"G Plitas","year":"2016","unstructured":"Plitas, G. et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 45, 1122\u20131134 (2016).","journal-title":"Immunity"},{"key":"2931_CR42","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1182\/blood-2004-07-2823","volume":"105","author":"L Piccio","year":"2005","unstructured":"Piccio, L. et al. Adhesion of human T cells to antigen-presenting cells through SIRP\u03b22-CD47 interaction costimulates T-cell proliferation. Blood 105, 2421\u20132427 (2005).","journal-title":"Blood"},{"key":"2931_CR43","doi-asserted-by":"crossref","first-page":"e8639","DOI":"10.1371\/journal.pone.0008639","volume":"5","author":"F Mercer","year":"2010","unstructured":"Mercer, F., Kozhaya, L. & Unutmaz, D. Expression and function of TNF and IL-1 receptors on human regulatory T cells. PLoS ONE 5, e8639 (2010).","journal-title":"PLoS ONE"},{"key":"2931_CR44","doi-asserted-by":"crossref","first-page":"6086","DOI":"10.1073\/pnas.1621280114","volume":"114","author":"Y Barsheshet","year":"2017","unstructured":"Barsheshet, Y. et al. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc. Natl Acad. Sci. USA 114, 6086\u20136091 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2931_CR45","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.immuni.2016.10.021","volume":"45","author":"M De Simone","year":"2016","unstructured":"De Simone, M. et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45, 1135\u20131147 (2016).","journal-title":"Immunity"},{"key":"2931_CR46","doi-asserted-by":"crossref","first-page":"E10672","DOI":"10.1073\/pnas.1810580115","volume":"115","author":"AM Magnuson","year":"2018","unstructured":"Magnuson, A. M. et al. Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. PNAS 115, E10672\u2013E10681 (2018).","journal-title":"PNAS"},{"key":"2931_CR47","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.cell.2016.09.050","volume":"167","author":"P Bacher","year":"2016","unstructured":"Bacher, P. et al. Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell 167, 1067\u20131078.e16 (2016).","journal-title":"Cell"},{"key":"2931_CR48","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1084\/jem.171.5.1393","volume":"171","author":"F Triebel","year":"1990","unstructured":"Triebel, F. et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 171, 1393\u20131405 (1990).","journal-title":"J. Exp. Med."},{"key":"2931_CR49","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1016\/S0959-8049(01)00184-8","volume":"37","author":"CE Demeure","year":"2001","unstructured":"Demeure, C. E., Wolfers, J., Martin-Garcia, N., Gaulard, P. & Triebel, F. T Lymphocytes infiltrating various tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of LAG-3\/MHC class II interactions in cell-cell contacts. Eur. J. Cancer 37, 1709\u20131718 (2001).","journal-title":"Eur. J. Cancer"},{"key":"2931_CR50","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/imr.12519","volume":"276","author":"LP Andrews","year":"2017","unstructured":"Andrews, L. P., Marciscano, A. E., Drake, C. G. & Vignali, D. A. A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80\u201396 (2017).","journal-title":"Immunol. Rev."},{"key":"2931_CR51","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.immuni.2004.08.010","volume":"21","author":"C-T Huang","year":"2004","unstructured":"Huang, C.-T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503\u2013513 (2004).","journal-title":"Immunity"},{"key":"2931_CR52","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.4049\/jimmunol.168.8.3874","volume":"168","author":"S Andreae","year":"2002","unstructured":"Andreae, S., Piras, F., Burdin, N. & Triebel, F. Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J. Immunol. 168, 3874\u20133880 (2002).","journal-title":"J. Immunol."},{"key":"2931_CR53","doi-asserted-by":"crossref","first-page":"5916","DOI":"10.4049\/jimmunol.180.9.5916","volume":"180","author":"B Liang","year":"2008","unstructured":"Liang, B. et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J. Immunol. 180, 5916\u20135926 (2008).","journal-title":"J. Immunol."},{"key":"2931_CR54","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.immuni.2018.07.007","volume":"49","author":"D Bauch\u00e9","year":"2018","unstructured":"Bauch\u00e9, D. et al. LAG3+ regulatory T cells restrain interleukin-23-producing CX3CR1+ gut-resident macrophages during group 3 innate lymphoid cell-driven colitis. Immunity 49, 342\u2013352.e5 (2018).","journal-title":"Immunity"},{"key":"2931_CR55","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1002\/art.40582","volume":"70","author":"F Ciccia","year":"2018","unstructured":"Ciccia, F. et al. Proinflammatory CX3CR1+CD59+ tumor necrosis factor-like molecule 1A+ interleukin-23+ monocytes are expanded in patients with ankylosing spondylitis and modulate innate lymphoid cell 3 immune functions. Arthritis Rheumatol. 70, 2003\u20132013 (2018).","journal-title":"Arthritis Rheumatol."},{"key":"2931_CR56","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/mi.2015.45","volume":"9","author":"J-S Do","year":"2016","unstructured":"Do, J.-S. et al. An IL-27\/Lag3 axis enhances Foxp3+ regulatory T cell-suppressive function and therapeutic efficacy. Mucosal Immunol. 9, 137\u2013145 (2016).","journal-title":"Mucosal Immunol."},{"key":"2931_CR57","doi-asserted-by":"crossref","first-page":"797","DOI":"10.4049\/jimmunol.0901233","volume":"183","author":"C Pot","year":"2009","unstructured":"Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol. 183, 797\u2013801 (2009).","journal-title":"J. Immunol."},{"key":"2931_CR58","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/art.1780300803","volume":"30","author":"GS Firestein","year":"1987","unstructured":"Firestein, G. S. & Zvaifler, N. J. Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. I. A cytofluorographic study of monocyte differentiation antigens and class II antigens and their regulation by gamma-interferon. Arthritis Rheum. 30, 857\u2013863 (1987).","journal-title":"Arthritis Rheum."},{"key":"2931_CR59","first-page":"19","volume":"78","author":"SC Knight","year":"1989","unstructured":"Knight, S. C. et al. Class II antigens on dendritic cells from the synovial fluids of patients with inflammatory arthritis. Clin. Exp. Immunol. 78, 19\u201325 (1989).","journal-title":"Clin. Exp. Immunol."},{"key":"2931_CR60","doi-asserted-by":"crossref","first-page":"6625","DOI":"10.4049\/jimmunol.169.11.6625","volume":"169","author":"EC Tsark","year":"2002","unstructured":"Tsark, E. C. et al. Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. J. Immunol. 169, 6625\u20136633 (2002).","journal-title":"J. Immunol."},{"key":"2931_CR61","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1136\/gut.2008.158824","volume":"58","author":"N Chaput","year":"2009","unstructured":"Chaput, N. et al. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58, 520\u2013529 (2009).","journal-title":"Gut"},{"key":"2931_CR62","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41586-019-1467-x","volume":"572","author":"N Saligrama","year":"2019","unstructured":"Saligrama, N. et al. Opposing T cell responses in experimental autoimmune encephalomyelitis. Nature 572, 481\u2013487 (2019).","journal-title":"Nature"},{"key":"2931_CR63","doi-asserted-by":"crossref","unstructured":"Joeris, T. et al. Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3+CD8+ Tregs. Sci. Immunol. 6, eabd3774 (2021).","DOI":"10.1126\/sciimmunol.abd3774"},{"key":"2931_CR64","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1002\/art.21972","volume":"54","author":"W Taylor","year":"2006","unstructured":"Taylor, W. et al. Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis Rheum. 54, 2665\u20132673 (2006).","journal-title":"Arthritis Rheum."},{"key":"2931_CR65","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1136\/ard.2010.133645","volume":"70","author":"M Rudwaleit","year":"2011","unstructured":"Rudwaleit, M. et al. The assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 70, 25\u201331 (2011).","journal-title":"Ann. Rheum. Dis."},{"key":"2931_CR66","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","volume":"177","author":"T Stuart","year":"2019","unstructured":"Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888\u20131902.e21 (2019).","journal-title":"Cell"},{"key":"2931_CR67","doi-asserted-by":"crossref","first-page":"D649","DOI":"10.1093\/nar\/gkx1132","volume":"46","author":"A Fabregat","year":"2018","unstructured":"Fabregat, A. et al. The reactome pathway knowledgebase. Nucleic Acids Res. 46, D649\u2013D655 (2018).","journal-title":"Nucleic Acids Res."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02931-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02931-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02931-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T04:44:26Z","timestamp":1674017066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-021-02931-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,14]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["2931"],"URL":"https:\/\/doi.org\/10.1038\/s42003-021-02931-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.05.31.444674","asserted-by":"object"}]},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,14]]},"assertion":[{"value":"22 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1395"}}