{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:55:41Z","timestamp":1790686541918,"version":"4.1.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>In spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27\/human \u03b22-microglobulin transgenic rat (B27-rat).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells (Tn).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon\/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1\/STAT3 transcription factors activity.\n                      <jats:italic>Stat1<\/jats:italic>\n                      mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas\n                      <jats:italic>Stat3<\/jats:italic>\n                      \/STAT3 expression increased upon disease establishment. Confirming the relevance of these results,\n                      <jats:italic>STAT1<\/jats:italic>\n                      mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Altogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells in SpA patients, thus offering new clues to better understand and treat SpA.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2023.1227281","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T14:05:08Z","timestamp":1697637908000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in 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