Butyrophilin Downregulation in Chronic Lymphocytic Leukaemia: An Important Barrier to <b>γδ</b> T Cell-Mediated Cytotoxicity

Introduction: Butyrophilins (BTNs) belong to the immunoglobulin superfamily; they play crucial roles in immune regulation, especially in γδ T cell activation. While their expression has been studied in solid tumours, their involvement in hematologic malignancies remains poorly understood. Objectives: We hypothesised that BTNs are dysregulated in chronic lymphocytic leukaemia (CLL), contributing to γδ T cell dysfunction and potentially influencing disease progression. Methods: In this study, we analyzed publicly available microarray and RNA-seq datasets to investigate the expression patterns of BTN genes in CLL. Results: Our findings reveal significant dysregulation of BTN gene expression in CLL, with BTN2A1, BTN3A1, BTN3A2, and BTN3A3 being markedly downregulated in peripheral blood mononuclear cells (PBMCs) and bone marrow samples from CLL patients compared to healthy volunteers, while BTN1A1 was upregulated. Furthermore, BTN2A2 was selectively downregulated in neoplastic B cells, whereas BTN3A1 was upregulated in T cells from CLL patients compared to healthy volunteers. Notably, lower BTN expression was associated with an unmutated IGVH status and male sex. Kaplan-Meier survival analysis demonstrated that higher expression of BTN2A1, BTN3A1, BTN3A2, and BTN3A3 correlated with a significantly longer overall survival. Conclusions: Given the established role of BTN2A1 and BTN3A1 in the phosphoantigen-mediated activation of Vδ2 γδ T cells, their downregulation may contribute to γδ T cell dysfunction in CLL. These results highlight the potential prognostic value of BTN gene expression in CLL and underscore the need for further studies exploring its mechanistic role in disease progression and immune evasion.