Beschreibung:
<jats:sec><jats:title>Introduction</jats:title><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 β2-microglobulin transgenic rat (B27-rat).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4<jats:sup>+</jats:sup> T cells (Tn). </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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. <jats:italic>Stat1</jats:italic> mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas <jats:italic>Stat3</jats:italic>/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, <jats:italic>STAT1</jats:italic> 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. </jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>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<jats:sup>+</jats:sup> T cells in SpA patients, thus offering new clues to better understand and treat SpA.</jats:p></jats:sec>