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Original Article

^a Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom
Lymphocyte Activation Laboratory, Rm. 105, Imperial Cancer Research Fund, 44 Lincolns Inn Fields, London WC2A 3PX, UK.44-020-7269-283144-020-7269-3231

d.cantrell{at}icrf.icnet.uk

During the early stages of thymopoiesis, cell survival is controlled by cytokines that regulate the expression of antiapoptotic proteins such as Bcl-2. At the pre-T cell stage, a critical checkpoint for β chain selection is monitored by the tumor suppressor p53: pre-T cells can survive and differentiate when p53 is removed genetically or when its proapoptotic function is inactivated physiologically as a consequence of signaling through the pre-T cell receptor complex. Previous work has shown that the guanine nucleotide binding protein Rho controls cell survival in T cell progenitors. Here we define the survival pathways controlled by Rho in pre-T cells and show that this GTPase is a pivotal regulator of the p53-mediated checkpoint operating at the time of β selection: loss of Rho function results in apoptosis in pre-T cells, but this cell death is prevented by loss of p53. The prevention of cell death by loss of p53 restored numbers of early T cell progenitors but did not fully restore thymic cellularity. Further analysis revealed that loss of Rho function caused survival defects in CD4/8 double-positive thymocytes that is independent of p53 but can be prevented by ectopic expression of Bcl-2. These studies highlight that the GTPase Rho is a crucial component of survival signaling pathways in at least two different thymocyte subpopulations: Rho controls the p53 survival checkpoint in pre-T cells and is also crucial for a p53 independent survival signaling pathway in CD4/8 double positives.

Key Words: pre-T cell • signaling • development • apoptosis • thymus

P.S. Costello and S.C. Cleverley contributed equally to this work.

R. Galandrini's present address is Dept. of Experimental Medicine and Pathology, University of Rome La Sapienza, V.le R. Elena, 324 Rome, Italy.

S.W. Henning's present address is Dept. of Molecular and Cell Biology, University of California, 415 Life Science Addition, Berkeley, CA 94720.

© 2000 The Rockefeller University Press

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