UC San Diego

Calcium ions (Ca²⁺) function as a universal second messenger in all eukaryotic cells, including cells of the immune system. Ca²⁺signals are crucial for peripheral T lymphocyte activation and effector functions, and in the developing thymus influence thymocyte selection and motility, yet the role of Ca²⁺signaling in early T lymphocyte development is not well understood. Here, we show that the Ca²⁺ion channels, inositol triphosphate receptors (IP₃Rs), are required for the differentiation and survival of T lymphocyte precursors in the thymus. Specifically, signaling via IP3Rs function to repress Sox13, an antagonist of the developmentally important transcription factor Tcf-1. Most importantly, in the absence of IP₃R-Ca²⁺signaling, the repression of key Notch transcriptional targets, including Hes1, fails to occur in post â-selection thymocytes, and IP₃R-deficient mice develop an aggressive T cell malignancy resembling human T cell acute lymphoblastic leukemia (T-ALL). Our data suggest a model where pre-T cell receptor derived Ca²⁺signals normally act to reinforce Tcf-1 expression and prevent malignant transformation of developing thymocytes. We also uncover previously unknown functions for IP₃R in the development of the red blood cell lineage, implicating IP₃R at the terminal stages of erythrocyte maturation. By establishing the requirement for IP₃R-Ca²⁺signaling in B cell development at the pre-BCR checkpoint, we have identified a common theme for Ca²⁺signaling in the regulation of early developmental checkpoints in lymphocytes