T Cell Dynamics during the Pretumor and Tumor Phase in the Murine Tcl1 Transgenic Chronic Lymphocytic Leukemia Model

Chronic lymphocytic leukaemia of B cells (B-CLL) is characterised by a clonal expansion of CD5-expressing B cells. However, the absolute number of T cells in patients with B-CLL is also increased, primarily due to an enlarged CD8+ population. Despite the enhanced number of T cells, they appear to be dysfunctional as they are largely devoid of anti-tumor activity and may even support the growth and maintenance of the malignant B-CLL clone. To further investigate the contribution this T cell dysfunction has on the establishment and progression of B-CLL, we monitored the changes in the T cell compartment in Eμ-TCL1 transgenic mice of various ages, during the progression of B-CLL-like disease. The deregulated expression of TCL1 in the B cell compartment of these mice leads to a hyperplasia of CD5+ CD19+ B cells early in life that is first detectable in the peritoneal cavity and later spleen and bone marrow. Later, this develops into a clonal disease, and onset of frank leukaemia, with infiltration of the CD5+ CD19+ cells into other organs (Bichi et al, 2003). Similar to human B-CLL, leukaemic TCL1 transgenic mice have increased absolute numbers of T cells, owing mainly to an expanded CD8+ population. Analyses of the cell surface expression of CD25, CD44, and CD62L, revealed a marked increase the number of memory and effector T cells compared to naïve T cells in the CD8+ subset that is also observed in the CD4+ subset, although to a lesser degree. Importantly, a decrease in the number of naïve T cells along with a corresponding increase in T memory and effector cells has been observed in the CD4+ T cell pool from patients with unmutated B-CLL (Tinhofer et al, unpublished), and the TCL1 mouse has been shown to be a model for the unmutated form of B-CLL. The relative shift from naïve to central memory T cells occurs alongside the CD5+ CD19+ hyperplasia in the TCL1 mice. In younger mice that exhibit the CD5+ CD19+ hyperplasia only in the peritoneal cavity, the changes in the T cell compartment are also observed solely within this organ. At later stages, when the CD5+ CD19+ hyperplasia has spread to other organs, the shift to memory T cells is also detectable in all infiltrated organs. Because memory and effector T cells represent antigen-experienced cells, we analysed the complementarity determining region 3 (CDR3) of the T cell receptor (TCR) of purified CD4+ and CD8+ populations by spectratyping in order to determine the degree of clonality (mono-, oligo-, or polyclonal) of the different T cell families within the T cell pool. More clonal T cells were observed in the CD8+ T cell subset in the infiltrated organs of leukaemic mice, though we could not observe a skewing towards any particular BV gene family. Interestingly, more mono- and oligoclonal CD4+ T cells have also been observed in the peripheral blood of patients with unmutated B-CLL. Thus, in many aspects, the TCL1 mouse recapitulates many of the T cell abnormalities observed in patients with B-CLL. It should be noted that, although driven from a B-cell specific promoter, the hTCL1 transgene is also expressed in the T cells of TCL1 mice. Interestingly, we have also found that TCL1 is overexpressed in the CD4+ and CD8+ T cells of patients with unmutated B-CLL compared to mutated CLL or healthy controls. Thus the Tcl1 transgenic murine CLL model seems suitable as a model for the immune aberrations found in human unmutated CLL.