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However, co-inhibitory molecule interactions between T cells and fibroblast-like synoviocytes (FLS) remain insufficiently understood. This study aimed to determine whether T cell activation and subset-associated cytokines differentially regulate the expression of PD-ligand 1 (PD-L1) and PD-L2 on FLS from RA patients compared with non-inflammatory (NI) controls, and whether PD1 engagement induces distinct transcriptional downstream responses in RA-FLS versus NI-FLS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Primary FLS cell lines were cultured from synovial tissue of patients with established RA or NI controls undergoing arthroscopy due to previous injury. Cells were cultured with CD3+\u2009T cells or stimulated with TNF, IFN\u03b3, IL-4, or TGF-\u03b2, and PD-L1 and PD-L2 expression was analysed by flow cytometry. PD-L1 and PD-L2 knockout FLS were generated using CRISPR\/Cas9. TNF-primed knockout or mock-transfected RA- and NI-FLS were treated with soluble PD1, and transcriptomic responses were analysed by total mRNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Analysis of publicly available RNA-sequencing datasets showed that, in early RA, PD-L1 and PD-L2 expression were significantly higher in lymphoid compared to myeloid and fibroid synovial tissue pathotypes. In established RA, PD-L1 and PD-L2 expression in FLS showed a trend towards higher levels in lymphocyte-rich compared to lymphocyte-poor tissue. In vitro, activated but not resting T cells upregulated both PD-L1 and PD-L2 on FLS. Further, TNF and IFN\u03b3 induced PD-L1 expression up to fourfold compared with unstimulated FLS, whereas IL-4 and TGF-\u03b2 had no effect. PD-L2 was induced by TNF, IFN\u03b3, and IL-4 to similar levels. PD-L1 and PD-L2 expression did not differ between RA- and NI-FLS either in co-culture with T cells or under cytokine stimulation. Finally, soluble PD1-induced reverse signalling in FLS altered the expression of threefold more genes in NI-FLS compared to RA-FLS, indicating that RA-FLS might be less responsive to PD1 signalling. PD-L1 or PD-L2 knockout further showed that reverse signalling through each ligand modulates distinct gene sets in FLS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Cytokine-induced PD-L1 and PD-L2 expression is preserved in FLS from established RA but PD1-ligand signalling is altered, potentially contributing to the loss of immune regulation in RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-026-03841-7","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T14:22:24Z","timestamp":1780410144000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytokine-induced PD-L1 and PD-L2 expression is preserved but reverse signalling is altered in rheumatoid arthritis fibroblast-like synoviocytes"],"prefix":"10.1186","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7969-4157","authenticated-orcid":false,"given":"Tilia","family":"Selld\u00e9n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8236-6089","authenticated-orcid":false,"given":"Anna-Karin","family":"Hultg\u00e5rd Ekwall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6707-159X","authenticated-orcid":false,"given":"Georgios","family":"Chatziagorou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-8266","authenticated-orcid":false,"given":"Anna-Carin","family":"Lundell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4137-1276","authenticated-orcid":false,"given":"Anna","family":"Rudin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"issue":"9","key":"3841_CR1","doi-asserted-by":"publisher","first-page":"2455","DOI":"10.1016\/j.celrep.2019.07.091","volume":"28","author":"MJ Lewis","year":"2019","unstructured":"Lewis MJ, Barnes MR, Blighe K, Goldmann K, Rana S, Hackney JA, et al. 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All patients gave informed consent to participation. No ethical approval was required according to the Swedish legislation section code 4\u00a73p SFS 2003:460 (Law on Ethical Testing of Research Relating to People) for samples collected anonymously at Sahlgrenska University Hospital, Gothenburg, Sweden.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"125"}}