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Immunological Memory

1. Pathways for Memory B cell Development
How do B cells progress to memory B cells after antigen exposure? To know the regulatory network responsible for memory B cell development, we have attempted to characterize memory B cell development by gene expression profiling, a possible approach for addressing the complexity of biological processes involved, in which multiple pathways are sequentially activated. To identify the changes in gene expression that take place in the transition from naive B cells to GC B cells, memory B cells or plasma cells upon antigen stimulation, we utilized Affymetrix GeneChip analysis, with linkage to gene cluster and network analysis. We detected a set of 100-200 transcripts enriched in antigen-stimulated B cell subsets to naive B cells. Q-PCR confirmation revealed prominent groups of genes with similar changes in their expression pattern within GC B cells, memory B cells and plasma cells upon antigen stimulation, such as the transcripts shared between GC B cells and memory B cells, or memory B cells and plasma cells, and the transcripts selectively enriched in either memory B cells alone or plasma cells alone.

Cis-regulatory analysis predicted the possible transcriptional factors responsible for the expression of the clusters of genes in memory B cells. We are interested in the role of early clusters of transcription factors in memory B cell development, because these factors may control subsequent rounds of transcriptional activation.


2. Identify the molecules responsible for memory B cell functions

We have cloned several genes which are highly expressed in memory B cells, including E52 (Fig. 2), 3940, 3023 and 4010. Over expression of E52, 3940 and 3023 in B cell lymphoma cell lines prolonged cell survival in proapoptotic culture conditions, which thereby led us to speculate that these genes are responsible for memory B cell survival. We are currently analyzing the B cell response in mice deficient with E52.

The 4010 gene encodes an adopter molecule and its overexpression in splenic B cells results in an augmentation of IgG1 response upon stimulation with anti-Igs and anti-CD40 mAbs in vitro. Thus, 4010 could be involved in the signaling cascade responsible for either memory B cell terminal differentiation or antibody secretion. To examine this possibility we are now establishing conditional knock out mice.


3. The origin of memory B cells.

Little is known about the origin of memory B cells. We have a collection of genetic markers for memory B cells and our time dependent gene profiling data support the view that memory B cell development takes place already at day 7 postimmunization. Using several techniques, we hope to soon reach definite conclusions in our understanding of the cellular process in memory B cell commitment and functional development.