Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1

Abstract

Abstract. The thymus is a central lymphoid organ in which T lymphocytes undergo differentiation and maturation without the need for antigenic stimulation. Apoptosis (programmed cell death), plays a critical role in shaping the T cell repertoire, deleting unproductive as well as potentially autoreactive T cells. Thymic atrophy has been observed in several model systems, including aging, graft-vs-host-disease and tumor development. However, the mechanisms involved in this phenomenon remain to be completely elucidated. We have previously shown that the progressive growth of D1-DMBA-3 mammary tumor leads to extreme thymic atrophy in the host. This thymic involution is associated with an early block in T cell maturation at the triple negative stage of differentiation. In the present study we have used our murine mammary tumor model to further analyze the specific T cell subpopulations present in the thymus of tumor-bearing animals as well as to characterize the alterations of the apoptotic process present during the impaired thymopoiesis associated to this thymic involution. Flow cytometric analysis revealed a moderate increase in the percentages of single positive CD4 + and CD8 + cells within the CD3 negative population in the thymuses of tumor-bearing mice. Moreover, we observed a prolonged increase in apoptosis among thymocytes from tumor-bearing mice compared with thymocytes from normal mice during tumor development. Lastly, we found a major decrease of Bcl-X L and A1, two crucial anti-apoptotic Bcl-2 family members that are developmentally regulated in T cells. Together, our data suggest that the severe thymic involution seen in mammary tumor bearers is due to an arrest in at least two steps of T cell differentiation and a down-regulation of important molecules that control programmed cell death.

Disruption of the Thymic Microenvironment Is Associated with Thymic Involution of Transitional Cell Cancer

“…This indicates that thymocyte development was arrested at the DN stage of differentiation. It has been observed that the impaired Jak/Stat signaling pathways and the decrease in Bcl-XL and A1 in the thymus of tumor bearers could contribute to abnormal T-cell differentiation and tumor-induced thymic atrophy [6,22,23]. Also, it has been suggested that Notch-1 and Jagged-1 signaling pathways can induce the apoptosis of thymocytes and influence the thymus development of the tumor bearer [5].…”