CD49d promotes T-cell senescence in chronic lymphocytic leukaemia.

Abstract

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.