ROLE OF TNF FAMILY MEMBERS IN MEMORY B CELL DEVELOPMENT

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In recent years, considerable attention has been focused on the factors involved in regulating the differentiation of naive B cells to the memory B cell compartment. Unfortunately, the study of memory B cell development has been difficult due to the extremely low frequency of these B cells. We have developed an in vivo model system in which the events of B cell differentiation occur at a high frequency, and thus will allow for the incisive evaluation of the requisite factors involved in establishing memory. The novel features of this system include the utilization of Ig transgenic B cells (referred to as QM B cells) which are antigen-specific, and have the ability to isotype switch and undergo somatic mutation. The underlying hypothesis to be tested is that TNF family members (TNFalpha, LTalpha, OX40L, CD40L) differentially regulate the generation and maintenance of memory B cells. The specific aims are two-fold: 1) to characterize QM B cells induced to differentiate into memory B cells in response to a T cell-dependent antigen, and 2) use blocking reagents to TNF family members to assess the stage(s) in which QM B cell differentiation is disrupted. These will be achieved by performing adoptive transfer experiments and phenotypic analysis will be assessed by flow cytometry and multi-color confocal imaging. QM B cell differentiation into the memory B cell pool will be examined by secondary transfer experiments and the capacity of QM B cells to generate high affinity, isotype switched, somatically mutated antibodies. These studies will elucidate factors involved in memory B cell differentiation, and contribute to vaccine development as well as immunotherapy for autoimmune disease.