CLL Cells in TCL1 Transgenic Mice Induce Similar Defects in CD4 and CD8 T Cells to Those Observed in Patients with CLL.

Abstract

Deregulation of the TCL1 pathway plays a crucial role in B-CLL pathogenesis and targeted expression of TCL1 results in the development in older mice of a B cell lymphoproliferative disorder resembling human B-CLL. CLL patients develop progressively impaired immunity and gene expression profiling of CD4 and CD8 T cells in B-CLL patients revealed defects in genes regulating critical pathways for T cell effector function. The onset of CLL in TCL1-transgenic mice also results in defects similar to those observed in CLL patients. Therefore, this murine model mimics the impact of CLL on the normal immune system, suggesting this may be an appropriate model to examine in vivo the impact of steps taken to repair T cell defects. In this study we examined whether infusion of CLL cells obtained from older mice induced similar changes in T cells of young mice, providing direct demonstration in vivo of interactions of CLL cells with the host immune system which result in development of immune deficiencies. Global gene expression profiling was performed using the Mouse 430_2 Affymetrix chip on highly purified CD4 and CD8 T cells from 6 non-transgenic mice and 16 TCL1 transgenic mice of different ages and at different stages in disease development and compared to that of cells from 6 TCL1 transgenic mice without CLL injected one week previously with 50 x 106 CLL cells. On unsupervised analysis using DNA-Chip Analyzer CD4 and CD8 T cells of young mice without CLL clustered with non-transgenic mice of different ages, whereas CD4 and CD8 cells from mice with developing or established CLL clustered with the young mice injected with CLL cells. Supervised analysis using Permax identified significant differences in expression for 628 genes (125 genes upregulated and 503 downregulated) in CD4 cells and 620 genes (320 genes upregulated and 300 genes downregulated) in CD8 cells in T cells from CLL bearing mice and CLL cell injected mice compared to non-transgenic mice and non-tumor bearing TCL1 mice. Comparison of pathways perturbed in the mice using GenMAPP finder compared to that observed in our previous studies in patients with CLL demonstrates similar alteration in many pathways, including regulation of cell proliferation and cell cycle control, cell differentiation, cytoskeleton formation, intracellular transportation and vesicle formation and transport. Examining these pathways functionally, we observed significantly decreased T cell proliferation, cytotoxicity and helper T cell function, increased numbers of CD4+CD25+CTLA4+ regulatory T cells and increased IL-4 amd IL-13 and decreased IL-12, IFNγ, sTNFRI, sTNFRII in CD4 cells and decreased IL-12p40, TIMP1 and TIMP2 in CD8 cells in both CLL bearing mice or mice injected with CLL cells compared to mice without CLL. These similar findings in human and murine CLL are in keeping with the hypothesis that interaction of the CLL cells with the normal immune function induces changes that result in decrease in T cell differentiation and effector function. It is intriguing to postulate that this effect diminishes autologous anti-tumor responses. We conclude that development of CLL in these transgenic mice induces T cell defects that mimic the defects that occur in CLL patients and that the TCL1 transgenic mouse model will serve as an ideal model to study steps to repair T cell function and their impact on CLL.