{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:09:34Z","timestamp":1785424174892,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,8]]},"group-title":"Immunology","reference-count":91,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 AR063676"],"award-info":[{"award-number":["R01 AR063676"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U19 AI110491"],"award-info":[{"award-number":["U19 AI110491"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 AR07826"],"award-info":[{"award-number":["R01 AR07826"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03qd7mz70","id-type":"ROR","asserted-by":"publisher"}]},{"award":["TRAM pilot award"],"award-info":[{"award-number":["TRAM pilot award"]}],"id":[{"id":"https:\/\/ror.org\/011pcwc98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rheumatoid arthritis (RA) is an autoimmune synovitis marked by anti-citrullinated protein antibodies (ACPAs) and infiltration of the synovium by activated immune cells. In ACPA-positive RA, CD8\u207a T cells are elevated in both the blood and synovium, and can be activated by MHC class I-restricted citrullinated autoantigens to mediate cytotoxic effector function. However, the mechanisms underlying the activation of cytotoxic CD8\u207a T cells in RA remain poorly understood. Here, single-cell transcriptomic and T cell receptor repertoire analysis of RA blood and synovial T cells revealed shared clonally expanded cytotoxic CD8\u207a T cell programs, with synovial enrichment of activated effector and proliferating populations and increased frequencies of\n                  <jats:italic>GZMB<\/jats:italic>\n                  \u207a\n                  <jats:italic>IFNG<\/jats:italic>\n                  \u207a CD8\u207a T cells. We demonstrated that RA-associated oral bacteria stimulate neutrophil extracellular trap (NET) formation, leading to the peptidyl arginine deiminases (PAD)-dependent generation of extracellular citrullinated bacterial and host proteins. We further demonstrated that these antigens can be cross-presented to CD8\u207a T cells via HLA class I molecules expressed by monocyte-derived dendritic cells (MoDCs) and autoreactive ACPA-expressing B cells. Toll-like receptor (TLR) signaling, particularly TLR4 activation by citrullinated antigens, enhanced cross-presentation of citrullinated antigens and promoted CD8\u207a T cell activation and clonal expansion. In turn, citrullinated antigens stimulated autoreactive B cells to produce IL-8, which recruited CXCR1\/2\u207a cytotoxic CD8\u207a T cells and amplified B cell-CD8\u207a T cell interactions. These findings reveal a mechanistic pathway linking microbial triggers, antigen presentation, and cytotoxic CD8\u207a T cell responses that may drive joint destruction in RA.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    TLR4-driven cross-presentation of citrullinated antigens by dendritic cells and autoreactive B cells promotes activation of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in rheumatoid arthritis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.03.729882","type":"posted-content","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T19:55:14Z","timestamp":1780948514000},"source":"Crossref","is-referenced-by-count":0,"title":["Cross-presentation of citrullinated antigens drives cytotoxic CD8\n                  <sup>+<\/sup>\n                  T cell responses in rheumatoid arthritis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1983-465X","authenticated-orcid":false,"given":"Jae-Seung","family":"Moon","sequence":"first","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA"},{"name":"VA Palo Alto Health Care System, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7082-3753","authenticated-orcid":false,"given":"Mengrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, USA"},{"name":"VA Palo Alto Health Care System, Palo Alto, CA, USA"},{"name":"Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, 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