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Thymocyte Negative Selection Is Mediated by Protein Kinase C- and Ca²⁺-Dependent Transcriptional Induction of Bim¹

Kirsten Canté-Barrett^*, Elena M. Gallo, Monte M. Winslow and Gerald R. Crabtree^2,*,

^* Departments of Developmental Biology and Pathology, Howard Hughes Medical Institute, and Program in Immunology, Stanford University, Stanford, CA 94305

The processes of positive and negative selection in the thymus both determine the population of T cells that will enter the peripheral immune system and eliminate self-reactive T cells by apoptosis. Substantial evidence indicates that TCR signal intensity mediates this cell fate choice: low-intensity signals lead to survival and differentiation, whereas high-intensity signals generated by self-Ag lead to cell death. The molecular mechanism by which these graded signals are converted to discrete outcomes is not understood. Positive selection requires the Ca²⁺-dependent phosphatase calcineurin, whereas negative selection requires the proapoptotic Bcl-2 family member Bcl-2-interacting mediator of cell death (Bim). In this study, we investigated the regulation of Bim expression and the role of Ca²⁺ in mediating negative selection. Our results show that transcription is necessary for both negative selection and Bim induction. Surprisingly, we also found that Ca²⁺ is necessary for Bim induction. Induction of bim transcription appears to involve protein kinase C, but not calcineurin, JNK, p38 MAPK, or MEK. These results localize the decision point in positive vs negative selection to a step downstream of Ca²⁺ signaling and suggest that negative selection signals induce Ca²⁺-dependent bim transcription through PKC.

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