{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T03:53:35Z","timestamp":1781754815193,"version":"3.54.5"},"reference-count":48,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Anti\u2010homocitrullinated protein\/peptide antibodies are specific to rheumatoid arthritis (RA) and predictive of worse prognosis, suggesting a pathogenic role for autoreactivity to homocitrullinated peptides (HomoCitP). However, T cell responses to HomoCitP remain largely unexplored. We investigated these responses in a humanized HLA\u2010DRB1*04\u2010transgenic (DR4tg) mouse model of RA, which expresses the strongest genetic risk factor for this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>DR4tg mice (n\u00a0=\u00a06\u201315) were injected subcutaneously with a HomoCitP called HomoCitJED, whereas control mice received phosphate\u2010buffered saline. After 10 days, T cells were analyzed for their phenotypic characteristics, cytokine production, and proliferative capacities in draining lymph nodes (dLNs) and spleens by flow cytometry, enzyme\u2010linked immunosorbent assays, and ProQuantum immunoassays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HomoCitJED immunization, compared with controls, drove robust expansion of T helper subsets in the dLNs, including more than a seven\u2010fold increase in Th1, Th17, and hybrid Th1\/Th17 cells (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0087). Cytokine staining confirmed effector activity, with higher frequencies of IL\u201017A+, TNF\u2010\u03b1+IL\u201017A+, and IFN\u2010\u03b3+IL\u201017A+ cells (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0207). Exhaustion\u2010associated markers were also increased, including lymphocyte activation gene\u20103 (LAG\u20103)+ and T cell Ig and mucin\u2010domain\u2010containing protein 3 (Tim\u20103)+ CD4+ T cells (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0411). CD8+ T cells mirrored these findings, with a six\u2010fold increase in CD25 and doubled killer cell lectin\u2010like receptor G1 (KLRG1) expression, accompanied by augmented IL\u201017A and IFN\u2010\u03b3\/IL\u201017A production and antigen\u2010specific proliferation (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0379). Expression of exhaustion\u2010associated markers Tim\u20103+ and LAG\u20103+ on CD8+ T cells was likewise elevated (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.0205).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HomoCitP elicited Th1\/Th17 and Tc1\/Tc17 responses marked by concurrent expression of activation and exhaustion\u2010associated markers, consistent with a dysregulated state. These findings position homocitrulline\u2010driven CD4+ and CD8+ T cell imbalance as a potential mechanistic contributor to RA pathogenesis and a target for future immunomodulatory therapies.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70239-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70239","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T13:05:42Z","timestamp":1780923942000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Homocitrullinated Peptides Drive Pro\u2010Inflammatory T Cell Responses in a Humanized Mouse Model of Rheumatoid Arthritis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1247-2599","authenticated-orcid":false,"given":"Sofya","family":"Ulanova","sequence":"first","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0577-8914","authenticated-orcid":false,"given":"Jaspreet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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Mansour","family":"Haeryfar","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"},{"name":"Department of Medicine, Division of Clinical Immunology and Allergy Western University  London Ontario Canada"},{"name":"Department of Surgery, Division of General Surgery Western University  London Ontario Canada"},{"name":"Department of Oncology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"},{"name":"Department of Pathology and Laboratory Medicine Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Cairns","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"},{"name":"Department of Medicine, Division of Rheumatology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8614-6972","authenticated-orcid":false,"given":"Lillian","family":"Barra","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Western University  London Ontario Canada"},{"name":"Department of Medicine, Division of Rheumatology Western University  London Ontario Canada"},{"name":"Department of Epidemiology and Biostatistics Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.220881"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/0300060515593258"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.170446"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.12.002"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.130742"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(03)00012-1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38637"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells7100161"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1129"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-024-01133-1"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.4.2053"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2015.10"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.4110\/in.2023.23.e41"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35264-8"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13645"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.6.2635"},{"key":"e_1_2_7_18_1","unstructured":"HillJA CairnsE BellDA inventors; London Health Sciences Centre Research Inc assignee.Peptides associated with MHC class II molecules involved in autoimmune diseases. 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