Bcl-2 family members are involved in the impaired T cell development in the thymuses of tumor bearing mice

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 1783 The thymus is the major site of T cell maturation; extensive proliferation, differentiation, and apoptosis occur in this organ. Thymocyte differentiation progresses through well-defined stages in which apoptosis are central to the selection of a functional TCR repertoire. During mammary tumorigenesis, there is a profound thymus involution associated with a severe depletion of the most abundant subset of thymocytes, CD4+CD8+ double positive (DP) immature cells. The life span of DP thymocytes depends on proper signals mediated first by the pre-TCR and then by the TCR. These signals ultimately regulate the expression of Bcl-2 family prosurvival members, which control susceptibility of DP cells to apoptosis. Previous results from our laboratory have reported that the thymic involution observed in tumor bearing mice is associated with an early block in T cell maturation, changes in the levels of cytokines expressed in the thymus microenvironment, and a minor increase in thymic apoptosis in tumor-bearers. In the present study we have used our well characterized murine D1-DMBA-3 mammary tumor model to better analyze the specific T cell subpopulations present in the thymus of tumor bearing animals. The expression of the different members of the Bcl-2 family was studied in the whole thymus during its involution in mammary tumor bearers. As shown before, flow cytometric analysis revealed a moderate increase in the apoptosis in thymuses of tumor bearing mice. Interestingly, our results show that Bcl-xL, a crucial protein that inhibits apoptosis during thymocyte development, is profoundly down-regulated in total thymuses of tumor hosts as compared to those of normal mice. Also, the protein for A1, another anti-apoptotic Bcl-2 family member that is developmentally regulated in T cells, is down-regulated in thymuses of tumor bearers. Collectively, our data suggest that the presence of the tumor induces changes in the levels of the Bcl-2 family members expressed in the thymus microenvironment contributing to the impaired T cell development in the thymuses of tumor bearers.