Difference in the Relative Distribution of CD4+ T-cell Subsets in B-CLL With Mutated and Unmutated Immunoglobulin (Ig) VH Genes

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is a clinically heterogeneous disease in which the clinical course is influenced by the presence or absence of immunoglobulin (Ig) variable heavy chain (VH) gene mutations. The poor clinical outcome of the subgroup with unmutated Ig VH genes has been linked to the persistent ability of the B-cell receptor in tumor cells from these cases to respond to antigen. As B-cell receptor signaling generally relies on T-cell help, we hypothesized that the course of B-CLL might not only be influenced by the Ig VH mutational status but also by the activation/differentiation status of T cells. We assessed the relative distribution of naive and memory T-cell subsets in peripheral blood from patients with mutated (M-CLL, n=71) and unmutated Ig VH genes (UM-CLL, n=42) and correlated it with the course of disease. We also compared the prosurvival potential of naive and memory T cells cocultured with B-CLL cells in vitro. A significant increase in relative numbers of central and effector memory T cells was observed in the CD4 T-cell pool from UM-CLL as compared with M-CLL cases and was associated with high Rai stage, progressive disease and shorter treatment-free survival (TFS). In a multivariate analysis, the relative number of CD4 central and effector memory T cells remained a significant prognostic parameter for TFS after correction for CD38 expression, Ig VH status, genomic aberrations, and Rai stage. The inverse correlation of memory CD4 T cells with TFS might be explained by their potential to support survival of B-CLL cells.

Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL

“…Similar to our earlier observation in human CLL, 10 we found a decrease in the relative numbers of naive T cells, from 80 to 70% in the CD4 þ compartment, and a concomitant increase in the relative numbers of antigen-experienced memory T cells and from 15 to 25% in the blood of TCL1 transgenic mice with established CLL compared with non-transgenic littermates (Table 1; Figures 2b-e). The effect was more pronounced in the CD8 þ T-cell subset, where the relative numbers of naive T cells was decreased to 39% compared with 69% in the WT mice, and the relative numbers of memory T cells increased to 61% from 27% in the controls (Table 1; Figures 2b-e).…”

“…10 In this work, we had detailed the shift from a naive to an antigen-experienced memory T-cell repertoire in human CLL on the CD4 þ cell side. The observed changes in CD4 þ composition were associated with more aggressive disease characteristics, and antigen-experienced CD4 þ cells were able to protect autologous CLL cells from dying in vitro, suggesting a potential pathophysiologic relevance of our observations.…”

“…9 Our own previous work suggested that in human CLL the T-cell subset composition is severely skewed and that this was associated with stage, progressive disease, and time to development of a treatment indication. 10 These data suggested that an accumulation of antigen-experienced T cells in the memory compartment were somehow associated with a more aggressive disease course.…”

IGHV unmutated CLL B cells are more prone to spontaneous apoptosis and subject to environmental prosurvival signals than mutated CLL B cells

“…39 It has already been reported that the course of CLL is influenced by the activation/differentiation status of T cells. 40 However, no data exist correlating the prosurvival effect of T cells with IGHV mutational status. Our results clearly demonstrate that the prosurvival effect of purified T cells on UM CLL B cells is mediated by restored translocation of NF-kB to the nucleus and partial recovery of Bcl-2 expression.…”

CD40-Mediated Activation of Chronic Lymphocytic Leukemia Cells Promotes Their CD44-Dependent Adhesion to Hyaluronan and Restricts CCL21-Induced Motility

“…CLL cells within lymphoid compartments display an activated CD69þ phenotype (2), and their proliferation occurs adjacent to CD40 ligand (CD40L) expressing CD4þ T cells and stromal cells within so-called proliferation centers (3,4). This and further evidence (5,6), led to the widely accepted concept that CD4þ T lymphocytes play an essential role in CLL cell activation, proliferation, and survival. CD40L, a TNF-a superfamily member expressed on activated T cells, has been described as a key mediator of T cell-driven CLL responses, acting in concert with T cell-derived cytokines (7)(8)(9)(10).…”