Deconstructing the allo-specific memory B cell response

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DESCRIPTION (provided by applicant): Deconstructing the allo-specific memory B cell response Allo-specific B cells and their antibody products are strongly predict with acute and chronic allograft rejection, especially in "sensitized" transplant recipients with pre-existing donr-specific antibodies (DSA). The source of antibody in the sensitized recipients derives from two distinct cellular pools: constitutive production of allo-specific antibody from the long lived plasa cell and de novo production from reactivated memory B cells in the recall response. While the long lived plasma cells can be viewed as a static population that produces a finite amount of antibody (life time times secretion rate), memory B cells represent a highly dynamic population that re- cycle indefinitely to produce bursts of antibody and to reseed the long lived plasma cell and memory B cell pools. Thus, we posit that understanding the roles of memory B cells under circumstances of transplantation, especially the mechanisms that regulate the dynamic behavior of allo-specific memory B cells, will ultimately prove to be important for controlling transplant rejection. Our work has uncovered a central regulator of B cell differentiation that controls the identity of differentiated B cells as a function of antigen affinity/avidity of the B cell antigen receptor (BCR). The Irf4 transcription factor controls the generation of plasma cells (PC) and Germinal Center B (GC B) cells by activating the expression of the rate limiting transcription factors important for those cell fates, Blimp-1 and Bcl6, respectively. We hypothesize that Irf4 plays a similarly critical role in controlling the generation of memory B cells as well as in controlling the dynamics of memory B cell reactivation. Furthermore, we have optimized a strategy to follow the fate of individual allogeneic MHC-specific B cells responding to transplants in mice. This technology has enabled us to quantify the proportions of PC, GC B, and memory B cells after primary and secondary immunizations. Therefore we propose to define the life cycle of allo-antigen specific memory B cells and how that may be altered by costimulation blockade, to identify the conditions with which memory B cells reactivate, and to determine the impact of memory B cells on mechanisms of humoral rejection.