Functional analysis of novel genes involved in the regulation of B cell activation and death

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To explore the molecular events that drive a resting B cell to enter the cell cycle, we have employed a modified subtractive cloning strategy to identify novel genes whose expression is regulated upon B cell activation through CD40, which interacts with CD40 ligand transiently expressed by activated T cells. In the past two years, we focused on the function in vivo of Clast1 and Clast5 genes. B cells from Clast1 tratnsgenic mice are hyper-reactive to antigen receptor signaling. In addition, both primary and secondary immune responses to T-dependent antigens are enhanced. These preliminary findings strongly suggest a role for Clast1 in augmenting B cell responses. In Clast5 transgenic mice, the size and cell number of both spleen and thymus are greatly reduced. Moreover, B cell responses to a variety of stimuli are impaired. Progenitor B cells in the bone marrow have a significantly reduced growth response to IL-7. These results indicate that Clast5 is a negative regulator of B cell activation and may serve to determine the threshold of B cell responses. We are in the process of generating Clast1 and Clast5 knock out mice.