Deficient function of Bruton's tyrosine kinase (Btk) results in the human B cell immunodeficiency, X-linked agammaglobulinemia (XLA), which is characterized by failure of developing and immature B cells to respond to signals controlling both the pre-B to immature B cells, and the naïve to activated B cell transitions. B cell activation, transcription, and proliferation are dependent upon the level and duration of the increased intracellular calcium ([Ca2+]i)which occurs in response to B cell antigen receptor (BCR) crosslinking. Our preliminary data demonstrate that Btk uniquely regulates sustained increases in [Ca2+]i and functions at a critical crossroads in the events regulating both positive and negative calcium signaling. Together, the failure of Btk-deficient cells to proliferate, and the Btk-dependent enhancement of sustained calcium signaling following BCR crosslinking suggest that Btk provides a calcium dependent signal(s) critical for B lineage survival and/or growth. In the proposed studies we will further define the mechanisms by which Btk family kinases maintain sustained calcium influx; identify the Btk-dependent downstream transcriptional events regulating B lineage development; and evaluate the developmental consequences of dysregulated Btk-dependent calcium signaling. A better understanding of these events will have important implications for both our understanding of normal immune cell development and ultimately for the management of XLA and other primary immunodeficiencies.
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