{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:09:06Z","timestamp":1773011346012,"version":"3.50.1"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"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:p>Chronic lymphocytic leukaemia (CLL) is an uncurable haematological malignancy and is associated with significant infection morbidity. Bruton\u2019s tyrosine-kinase inhibitors (<jats:italic>e.g.<\/jats:italic>, ibrutinib) have improved disease outcomes, but severe infections and poor immunization responses afflict patients. Recently, carriage of the endemic <jats:italic>Staphylococcus aureus<\/jats:italic> (SA) was associated with lymphocytosis and decreased survival in CLL patients. We then hypothesized that exposure to staphylococcal superantigens (SAgs), known to promote hyper-inflammatory responses, impairs immunity and increases severe infection risk in CLL patients. Herein, we evaluate the reactivity of T cells and CLL cells to SA SAgs, in cultures derived from ibrutinib-treated and untreated CLL patients. We found that ibrutinib-treated patients had less naive CD8+ T cells (p=0.0348), more checkpoint receptor (TIM-3) expression in memory T cells (p&amp;lt;0.0001), and lower IFN\u03b3\/cytokine responses in patient T cells (p\u22640.0298). Exposure to SA SAg further increased the accumulation of memory T cells with an exhaustion-phenotype, preferentially in cultures derived from ibrutinib-treated patients (p\u22640.0350). Nevertheless, staphylococcal SAgs could not induce regulatory T cells from CLL patients inasmuch as healthy donors (p\u22640.0461) and this was associated with accumulation of inflammatory T cells. Significantly, SAg-exposure enhanced inflammatory activation of CLL tumour cells, which acquired CD38, CD40, CD86, while downregulating CD27 (p\u22640.005), even in cultures from ibrutinib-treated CLL patients. Thus, we suggest that environmental SAg-exposure promotes the accumulation of pseudo-exhausted T cells, which induce\/sustain tumour cell activation, not counteracted by ibrutinib. Our study critically helps understand the chronic inflammatory milieu in CLL patients, with implications for infection morbidity, disease aetiology and future interventions.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1531059","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T06:47:14Z","timestamp":1742971634000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Ibrutinib enhances the bias of T cell responses towards staphylococcal superantigens sustaining inflammation in chronic lymphocytic 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