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Published online before print November 7, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1005585

Received for publication October 17, 2005.
Revised September 20, 2006.
Accepted for publication October 5, 2006.

Article

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 ^*@, Kouhei Sakai ^*, Seiji Kitahara ^*, Michael S. Patrick ^*, Yoshinao Azuma ^*, Kazuro Sugi , Toshio Kitamura , Jonathan Kaye , and Mutsunori Shirai ^*

*Department of Microbiology & 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

^@ To whom correspondence should be addressed. E-mail: hsuzuki{at}ri.imcj.go.jp.

	Abstract

Rac1, one of the Rho family small guanosinetriphosphatases, 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