BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes

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From: Nature(Vol. 415, Issue 6874)
Publisher: Nature Publishing Group
Document Type: Article
Length: 4,607 words
Lexile Measure: 1620L

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Author(s): Philippe Bouillet [1]; Jared F. Purton [2]; Dale I. Godfrey [2]; Li-Chen Zhang [1]; Leigh Coultas [1]; Hamsa Puthalakath [1]; Marc Pellegrini [1]; Suzanne Cory [1]; Jerry M. Adams [1]; Andreas Strasser (corresponding author) [1]

During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy) [1], or can be deleted from the repertoire by cell death [1]. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)-CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis) [2, 3, 4], but the mechanisms ensuring this 'negative selection' are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim [5, 6] (also known as Bcl2l11) are refractory to apoptosis induced by TCR-CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL , inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.

Two distinct but converging signalling pathways activate the aspartate-specific cysteine proteases (caspases) that mediate apoptosis [7, 8]. Engagement of certain receptors belonging to the tumour-necrosis factor receptor (TNF-R) family, such as CD95 (also known as Fas/APO-1) or TNF-R1, activates caspase-8 through the adapter protein FADD/MORT1. This pathway seems dispensable for negative selection, however, because autoreactive thymocytes lacking FADD or caspase-8 function are deleted normally [9, 10, 11]. Instead, negative selection probably involves the stress-induced apoptotic pathway, which activates caspase-9 through the scaffold protein Apaf-1 (apoptotic protease-activating factor 1), and is regulated by members of the Bcl-2 family of proteins [7, 8]. As overexpression of Bcl-2 impairs the thymocyte death that is induced by TCR-CD3 stimulation [12, 13], pro-apoptotic Bcl-2 family members might be the critical initiators of apoptosis in negative selection. Recent genetic and biochemical findings have shown that apoptosis is initiated by 'BH3-only' Bcl-2 family members, which share with their relatives only the short BH3 interaction domain [14]. Pro-apoptotic Bax and Bak, which are structurally more akin to the anti-apoptotic Bcl-2 family members [7], act downstream in the cell death programme [15].

We were prompted to investigate the role of the BH3-only protein Bim in thymocyte-negative selection when disruption of the Bim gene showed that Bim is a critical regulator of lymphocyte homeostasis, serves as a barrier against autoimmune disease, and is necessary for the apoptotic response to certain stress signals [6]. The marked resistance of Bim-deficient thymocytes to killing by the calcium ionophore ionomycin [6] was particularly interesting, because calcium flux elicited by TCR engagement is thought to initiate the deletion of autoreactive thymocytes [16]. One widely used model of negative selection is exposure of thymocytes in vivo or in vitro to anti-CD3 antibody, which aggregates the TCR-CD3...

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Gale Document Number: GALE|A187492597