The differentiation and survival of long-lived plasma cells

During an immune reaction to an invading pathogen, a population of lymphocytes with receptors that specifically recognize the pathogen are activated and become memory cells. Characteristically, memory lymphocytes persist for long periods of time and retain their capacity to specifically recognize the immunizing pathogen. The longevity and specificity of these lymphocytes provide long-lived, specific protection from repeated infections by the invading pathogen. While memory lymphocytes play an important role in the immune system, very little is known about their generation or regulation. Within the humoral arm of the immune system, memory results from the accumulation of long-lived, quiescent antigen-specific B cells (memory B cells) and the production of antibodies by long-lived plasma cells. Thus, humoral immune memory involves the activation of long-lived memory B cells capable of recognizing a specific pathogen and the formation of long-lived plasma cells which produce antibody capable of neutralizing that same pathogen. The importance of long-lived plasma cells' contribution to overall humoral memory is unknown. The studies presented investigate the cells and factors that are critical for the generation and longevity of long-lived plasma cells. Through the use of immunoglobulin transgenic B cells, we were able to track the progression of an immune response within an immune host. Analysis within the immune host allowed us to identify intermediary stages of development between germinal center B cells and long-lived plasma cells. One of the post-GC subsets that was isolated in these immune mice represented B cells that were precursors to plasma cells. We ascertained the identity of the precursors by their ability to produce functional plasma cells following secondary adoptive transfer and their phenotypic characteristics. Further analysis resulted in the identification of mechanisms regulating plasma cell precursor differentiation and plasma cell formation. Subsequent studies revealed factors within the BM that were essential for sustaining the longevity of PCs. These findings not only provide important information on formation of immune memory but also implicate novel pathways regulating induction of autoimmunity and multiple myeloma.