Cell-mediated immunity in chronic lymphocytic leukemia

Although there has been a rapid increase in knowledge of the biology of the malignant B-lymphocyte in chronic lymphocytic leukemia (CLL), we still lack a clear understanding of the role of non-malignant lymphocytes in the pathogenesis of CLL. The first clinically significant immune defect in CLL is usually hypogammaglobulinemia, but qualitative and quantitative defects in T and NK cells in CLL patients have been recognized for decades [1], can occur early in the course of CLL, and have even been reported in patients with monoclonal B cell lymphocytosis [2]. However, the investigation of the clinical implications of these changes has only recently begun. Patients with CLL have early and profound changes in blood T and NK cell counts. Absolute counts of both T and NK cell counts are increased. Among T cells, CD8þ cells are increased more than CD4þ cells resulting in a decrease in the CD4:CD8 ratio [3]. The absolute counts of regulatory T cells (Treg) are also significantly increased [4]. While similar changes do occur with aging of the immune system, the magnitude of the changes in patients with CLL are clearly pathological. The mechanisms of these changes in T and NK cells are not well understood. CLL cells interact directly with non-malignant lymphocytes, can act as antigen presenting cells, and secrete cytokines that could alter T and NK cell numbers, subtype ratios and function. In addition, the impaired humoral and cell-mediated immunity in patients with CLL increases the overall risk of infection and especially the risk of reactivation of latent cytomegalovirus (CMV) infection. CMV reactivation increases the levels of cytotoxic CD8þ and CD4þ T cells with a considerable number of these cells being CMV antigen specific [3,5]. However, there is no direct evidence of other infections altering T cell counts [5]. There is still no convincing data that the changes in T and NK cells counts seen in CLL comprise an effective immune response against tumor cells [3,5]. In contrast, the increased numbers of functionally normal Treg could potentially inhibit any anti-tumor cell immune effect [4,6]. The available data thus show that non-malignant lymphocyte biology in patients with CLL is markedly disordered. The consequent immunodeficiency increases the risk of infection and possibly second malignancies, and is unlikely to provide effective anti-tumor immunity. Because of the potential importance of abnormalities in non-malignant lymphocytes in patients with CLL, there could be a clinical value in quantifying these defects and correlating them with a clinical outcome. In this issue of Leukemia and Lymphoma, Gonzalez et al. report the T and NK cell counts in a cohort of patients with CLL and examine the relationship between lymphocyte subtype ratios and survival [7]. Their study shows that the ratios of CD4þ T cells, CD8þ T cells, and NK cells compared to CLL cells are significantly increased in earlier stage CLL and that higher CD4þ and CD8þ: CLL ratios are independent predictors of survival on multivariate analysis. However, only the absolute CD8þ T cell count (but not the absolute CD4þ T cell count) was associated with better survival. The strengths of this study include the representative age at diagnosis, cohort size, duration of follow up, and the correlation the measured parameters with survival rather than time to first treatment. In addition, this study is a confirmation and extension of previously published work [8]. The major concern