In normal T-cell development, thymic epithelial cells (TECs) exert an inductive role in migration, survival and maturation of thymocytes through the generation of a local gradient of cytokines and the establishment of adhesive interactions with immature T cells. Interleukin- 7 (IL-7), secreted by thymic stromal cells, has a nonredundant role in regulating the early phases of T-cell dif- ferentiation. Furthermore, it is known that IL-7 promotes survival and induces cell cycle progression of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study we analysed the role of IL-7 on T-ALL blast survival with- in the microenvironment generated by T-ALL-TEC interaction. To this aim T-ALL blasts derived from 10 adult patients were cultured with TECs obtained from human normal thymuses. The level of blast apoptosis was measured by annexin V-PI co-staining and flow cytometry. The proliferative response of leukemic cells to TEC inter- action was evaluated by 3H-TdR incorporation at various time intervals of culture. To assess the role of IL-7, lympho-epithelial co-cultures were carried out in the presence of anti-IL-7 or anti IL7-R blocking antibodies and T-ALL blasts were then analysed for the apoptosis level. When T-ALL cells were cultured in the presence of TEC monolayers, the percentage of viable cells were sig- nificantly increased and this protection was sustained with time in culture. In addition, the interaction with TECs induced a considerable proliferative response in T- ALL cells (15-fold the control cells after 7 days of cul- ture). The presence of IL-7 or IL-7R blocking antibodies in lympho-epithelial co-cultures consistently reduced the extent of TEC-mediated protection in T-ALL blasts (70% decrease). These results show that IL-7-IL7-R interplay has the major role in the modulation of T-ALL survival within the microenvironment generated by the T-ALL-TEC interaction.

Thymic epithelial cell-derived interleukin-7 promotes survival of human T-cell acute lymphoblastic leukemia

SCUPOLI, Maria;VINANTE, Fabrizio;KRAMPERA, Mauro;NADALI, GIANPAOLO;ZAMPIERI, FRANCESCA;SANTINI, Francesco;PIZZOLO, Giovanni
2003

Abstract

In normal T-cell development, thymic epithelial cells (TECs) exert an inductive role in migration, survival and maturation of thymocytes through the generation of a local gradient of cytokines and the establishment of adhesive interactions with immature T cells. Interleukin- 7 (IL-7), secreted by thymic stromal cells, has a nonredundant role in regulating the early phases of T-cell dif- ferentiation. Furthermore, it is known that IL-7 promotes survival and induces cell cycle progression of T-cell acute lymphoblastic leukemia (T-ALL) cells in vitro. In this study we analysed the role of IL-7 on T-ALL blast survival with- in the microenvironment generated by T-ALL-TEC interaction. To this aim T-ALL blasts derived from 10 adult patients were cultured with TECs obtained from human normal thymuses. The level of blast apoptosis was measured by annexin V-PI co-staining and flow cytometry. The proliferative response of leukemic cells to TEC inter- action was evaluated by 3H-TdR incorporation at various time intervals of culture. To assess the role of IL-7, lympho-epithelial co-cultures were carried out in the presence of anti-IL-7 or anti IL7-R blocking antibodies and T-ALL blasts were then analysed for the apoptosis level. When T-ALL cells were cultured in the presence of TEC monolayers, the percentage of viable cells were sig- nificantly increased and this protection was sustained with time in culture. In addition, the interaction with TECs induced a considerable proliferative response in T- ALL cells (15-fold the control cells after 7 days of cul- ture). The presence of IL-7 or IL-7R blocking antibodies in lympho-epithelial co-cultures consistently reduced the extent of TEC-mediated protection in T-ALL blasts (70% decrease). These results show that IL-7-IL7-R interplay has the major role in the modulation of T-ALL survival within the microenvironment generated by the T-ALL-TEC interaction.
Leukemia; microenvironment; cell survival
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/952041
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