An investigation of T cell dysregulation in B-cell chronic lymphocytic leukaemia

Abstract

B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by an accumulation of clonal malignant B cells within lymphoid tissue, the bone marrow and the peripheral blood. Whilst abnormalities of these B cells are the essential cause of this disease, the aim of this research project was to investigate whether the T cell compartment may play a role in the aetiology of this disease by evaluating the expression of key surface antigens involved in both activation of and interaction with B cells and other antigen presenting cells of the immune system. There were marked abnormalities in the expression of certain key activation and interaction antigens on the peripheral blood T cells of patients with B-CLL, in particular, compared to normal controls, there was a significant reduction in the number of circulating T cells expressing CD25, CD28, CD152, CD4, CD5 and CD11a. There was no difference in expression of TCRαβ, CD8, CD54 and CD154. Significantly more T cells from CLL patients expressed HLA-DR. Removal of the malignant clone of cells prior to short-term T cell culture did not affect expression of these markers. Numbers of T cells expressing intracellular CD25 and CD152 were not decreased after activation and a significantly greater number of resting T cells expressed both antigens intracellularly. There was also evidence of a soluble factor present in CLL AB serum which caused increased numbers of normal and CLL T cells to express CD25 and CD152 after culture. Initial results suggest that this may be IFN-γ, levels of which were significantly higher, as measured by ELISA, from resting CLL T cells compared to normals. By studying the expression of these antigens using cell culture, flow cytometric and ELISA techniques, the results suggest a functional state of anergy in these T cells. This anergic state may contribute to the pathogenesis of B-CLL and its related phenomena of immunosuppression and autoimmunity. This was further reflected in the results of the T cell functional studies and reduced IL-2 expression in the mixed lymphocyte reaction (MLR).