Bcl-2 Counters Apoptosis by Bax Heterodimerization-dependent and -independent Mechanisms in the T-cell Lineage

doi:10.1074/jbc.272.46.29347

Bcl-2 Counters Apoptosis by Bax Heterodimerization-dependent and -independent Mechanisms in the T-cell Lineage*

From the Departments of ^‡Pathology and ^§Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611

Abstract

The effect of the cell death inhibitor Bcl-2 in relation to its capacity to dimerize with apoptosis promoter Bax or its homologs at their physiological expression levels was explored in the T-cell lineage. Transgenic mice expressing a BH1 mutant Bcl-2 (Bcl-2 mI-3), which fails to heterodimerize with proapoptotic members of the Bcl-2 family, such as Bax, were generated. Bcl-2 mI-3 protected immature CD4⁺8⁺ thymocytes from spontaneous, glucocorticoid and anti-CD3-induced apoptosis and altered T cell maturation, resulting in increased percentages of CD3^hi and CD4⁻8⁺ thymocytes. In contrast, apoptosis of peripheral T-cells was unaffected by transgene expression. This correlated with their high Bax expression level and insensitivity to the caspase inhibitor, zVAD-fmk, a functional hallmark of Bax-like activity. Thus, within the T-cell lineage Bcl-2 can inhibit apoptosis independent of its association with Bax or its homologs; yet, above a threshold level of their physiologic proapoptotic activity, the capacity of Bcl-2 to heterodimerize with Bax or its homologs appears essential for it to counter cell death.

Footnotes

↵* This work was supported in part by National Cancer Institute Grants CA71890-01 and CA72535-01 (to Z. N. O.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¶ To whom correspondence should be addressed: Dept. of Pathology, Northwestern University Medical School, Ward Bldg. 6-204, W127, 303 East Chicago Ave, Chicago, IL 60611. E-mail:zno008{at}lulu.acns.nwu.edu.
↵1 The abbreviations used are: BH1, BH2, BH3, Bcl-2 homology 1, 2, and 3 domains, respectively; wt, wild type; FITC, fluorescein isothiocyanate; PE, phycoerythrin; mAb, monoclonal antibody; pAb, polyclonal antibody; FCS, fetal calf serum; IL, interleukin; TCR, T-cell receptor.
- Received May 19, 1997.
- Revision received August 15, 1997.