CD49d promotes T‐cell senescence in chronic lymphocytic leukaemia

While CD49d (α4 integrin) is an established prognostic marker in chronic lymphocytic leukaemia (CLL) and is associated with aggressive disease, its impact on T-cell biology remains poorly understood. Compared to healthy donors, CLL patients exhibited significantly elevated CD49d expression in both CD4+ and CD8+ T cells (p < 0.001) as detected by flow cytometry, which was also confirmed by the single-cell RNA sequencing (scRNA-seq) (p < 0.001). Differentially expressed genes in CD49d+ T (both CD8+ and CD4+ T cells) versus CD49d- T cells identified in CLL patients were enriched in cellular senescence pathways, while this phenomenon is absent in healthy individuals. Functional validation demonstrated that CD49d+ T cells displayed elevated senescence-associated markers (e.g. interferon-gamma, granzyme B) and a shift towards memory phenotypes, correlating with immunosuppressive signatures. This discovery suggests that targeting CD49d-dependent senescence pathways may reverse T-cell dysfunction in CLL immunotherapy.