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Published online before print November 7, 2006

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(Journal of Leukocyte Biology. 2007;81:500-508.)
© 2007 by Society for Leukocyte Biology

Rac1-mediated Bcl-2 induction is critical in antigen-induced CD4 single-positive differentiation of a CD4⁺CD8⁺ immature thymocyte line

Hiroyo Oda^*, Harumi Suzuki^*,1, Kouhei Sakai^*, Seiji Kitahara^*, Michael S. Patrick^*, Yoshinao Azuma^*, Kazuro Sugi, Toshio Kitamura, Jonathan Kaye and Mutsunori Shirai^*

^* Department of Microbiology and Immunology, Yamaguchi University School of Medicine, Ube, Japan;
Department of Clinical Research, National Sanyo Hospital, Ube, Japan;
Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA

¹ Correspondence at current address: Department of Pathology, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. E-mail: hsuzuki{at}ri.imcj.go.jp

Rac1, one of the Rho family small guanosine triphosphatases, has been shown to work as a "molecular switch" in various signal transduction pathways. To assess the function of Rac1 in the differentiation process of CD4 single-positive (CD4-SP) T cells from CD4CD8 double-positive (DP) cells, we used a DP cell line DPK, which can differentiate into CD4-SP cells upon TCR stimulation in vitro. DPK expressing dominant-negative (dn)Rac1 underwent massive apoptosis upon TCR stimulation and resulted in defective differentiation of CD4-SP cells. Conversely, overexpression of dnRac2 did not affect differentiation. TCR-dependent actin polymerization was inhibited, whereas early ERK activation was unaltered in dnRac1-expressing DPK. We found that TCR-dependent induction of Bcl-2 was suppressed greatly in dnRac1-expressing DPK, and this suppression was independent of actin rearrangement. Furthermore, introduction of exogenous Bcl-2 inhibited TCR-dependent induction of apoptosis and restored CD4-SP generation in dnRac1-expressing DPK without restoring TCR-induced actin polymerization. Collectively, these data indicate that Rac1 is critical in differentiation of CD4-SP from the DP cell line by preventing TCR-induced apoptosis via Bcl-2 up-regulation.

Key Words: T lymphocytes • TCRs • apoptosis • thymus