A star is born in Bim

Abstract

As soon as they express their novel T-cell receptors (TCRs) in the thymus, immature T cells are screened for autoreactivity in a process known as negative selection. Although the precise signals that connect TCR stimulation to an apoptotic program are still being clarified (and might differ by developmental stage), there is general agreement that high-affinity interactions between the TCR and thymic MHC–peptide complexes ultimately trigger mitochondrial activation of a caspase complex and subsequent apoptosis. Bcl-2 family members are crucial upstream regulators of these mitochondria-mediated death signals. Antiapoptotic family members bcl-2 and bcl-xL can protect thymocytes from some TCR-mediated apoptotic signals and were the main focus of early studies into the regulation of negative selection. However, more and more attention has been paid to the proapoptotic family members, which include bcl-2-like members (e.g. bax and bak) and more distant cousins that share only one domain (BH3) with bcl-2 family members (e.g. the ‘BH3-only members’, bid, bik and bim). This attention appears well deserved.There was a general expectation that redundancy within the large family of proapoptotic bcl-2 family members would confound efforts to assign a particular role to a specific bcl-2 family member. Surprisingly, however, Bouillet et al. [1xBH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Bouillet, P. et al. Nature. 2002; 415: 922–926Crossref | PubMed | Scopus (544)See all References][1] reveal that a single BH3-only member, Bim, is required for thymocyte negative selection. In each of six models of negative selection examined, Bim deficiency abrogated thymocyte apoptosis. Bim-knockout thymocytes are protected from in vitro TCR-mediated apoptosis. Bim-knockout mice are unable to delete thymocytes specific for superantigen and for peptide antigen in vivo. Negative selection of MHC class I- and MHC class II-restricted thymocytes does not occur in the absence of Bim. Although T-cell maturation is not always fully restored in Bim?/? mice (raising the possibility that other mechanisms of negative selection can play a role at later stages of development), Bim is clearly a main actress in the thymocyte apoptosis drama.How does Bim fit into the TCR-signaling cascade? Bouillet et al. provide evidence that TCR signals can upregulate Bim expression post-transcriptionally, and can induce its translocation from cytoskeleton to mitochondria. However, the proximal TCR signals responsible for these crucial changes are unknown. Similarly, the downstream targets of Bim have not yet been identified. BH3-only family members generally appear to act as mitochondria-mediated apoptosis initiators by enhancing proapoptotic and/or inhibiting antiapoptotic activity of bcl-2-like family members. Although these investigators found no evidence for a physical association between Bim and the proapoptotic bcl-2 family members bax and bak, which gained recent prominence as crucial apoptosis mediators, it will be interesting to see if they have a functional relationship. Nonetheless, Bouillet et al. have made a star out of the previously under-appreciated Bim, and attention will now undoubtedly be riveted on its future.