Vaccines that induce antibody-mediated immunity have drastically improved human health. However, successful vaccines exist for only a fraction of pathogens and even the most successful vaccines exhibit drastic variability. For example, some vaccines induce levels of protective antibody that varies 10,000-fold from person-to-person. Another example of variability is that some vaccines induce long-lived immunity while others require life-long re- vaccination. The key to understanding these differences in protective immunity is to understand the development and persistence of the long-lived lymphocytes that confer protection. Antibody-mediated immunity relies on the proper development and persistence of long-lived """"""""memory"""""""" B cells and antibody-secreting plasma cells. Unlike plasma cells, memory B cells respond to secondary pathogen encounter and differentiate quickly into antibody secreting cells. Despite this importance in protective immunity, the mechanism of memory B cell differentiation is not well understood. The objective of this proposal is to identify and characterize developing memory B cells. This is important because access to developing memory B cells will allow us to identify molecules important for this transition that are not readily apparent from the study of fully developed memory cells. Memory B cells are the long-lived, quiescent progeny of cell death-susceptible, proliferating precursors. It is unknown how or when developing memory B cells exit cell cycle and upregulate an anti-apoptotic program. The central hypothesis of this application is that """"""""memory precursor"""""""" B cells can be identified as non-quiescent cells that have adopted the survival program and cell surface phenotype of bona fide memory cells. Therefore, my specific aims are: 1. Determine when quiescent memory B cells arise from proliferating precursors. And 2. Determine when developing memory B cells upregulate a survival program that allows these cells to avoid cell death. The proposed studies are innovative because cutting edge enrichment techniques will be utilized to analyze the development of memory B cells without the aide of artificially increasing the starting number of cells. At the completion of these studies I will have a complete understanding of the kinetics of memory cell development and will have begun to probe the role of candidate molecules in this process.
Vaccination aims to induce the development of long-lived cell populations that confer protection against the select agent (pathogen/protein/etc.) of interest. In this proposal I will probe the functional development of one of these long-lived populations to determine the mechanism by which these cells develop. The long-term goal of this work is to understand the development of these cells such that vaccines can be designed to maximize protective responses.
|Taylor, Justin J; Pape, Kathryn A; Jenkins, Marc K (2012) A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med 209:597-606|
|Taylor, Justin J; Martinez, Ryan J; Titcombe, Philip J et al. (2012) Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen. J Exp Med 209:2065-77|
|Pape, Kathryn A; Taylor, Justin J; Maul, Robert W et al. (2011) Different B cell populations mediate early and late memory during an endogenous immune response. Science 331:1203-7|