Although the generation of both plasma and memory B cells results from an initial antigenic stimulus, these cells migrate to separate locations, have different co-stimulation requirements and may even be derived from separate precursor populations. Thus, in developing vaccination strategies for sustained humoral immunity, the production of both antibody secreting effector cells as well as long-lived memory B cells must be optimized. Unfortunately, the mechanisms that induce activated B cells to enter either the plasma or memory cell differentiation pathways are unknown. We do know, however, that the engagement of CD40 on B cells by its ligand on activated T cells is necessary for successful T dependent immunity and is also one of the most potent triggers of B cell activation. Furthermore, although CD40 signaling is critical for germinal center formation and the production of memory B cells, its ability to directly regulate the differentiation pathway of activated B cells rather than simply promoting their survival/expansion remains controversial. Our preliminary observations indicated that sustained signaling through CD40 effectively blocks the B cell terminal differentiation pathway in vitro. We have hypothesized that CD40 signaling alters the developmental fate of responding B cells and that this is most obvious in the germinal center, where CD40 triggered B cells proliferate and undergo selection, but do not secrete antibody. The experiments in this proposal will directly examine the role of CD40 signaling in regulating the developmental fate of activated B cells and will determine when and where the inhibitory influence of CD40 signaling is evident in the immune response. We will first examine how CD40/gp39 interactions influence B cell differentiations in a previously established in vitro co-culture system and then confirm these results in vivo using blocking antibodies or the adoptive transfer of gp39/CD40 deficient lymphocytes. Furthermore, since CD40 triggering is mediated through contact with gp39 expressing cells, we will determine the factors that regulate gp39 expression on activated lymphocytes and examine how these conditions influence B cell differentiation in vitro and in vivo. Finally, we will examine the molecular mechanisms through which CD40 signaling mediates its biological effects. These results should enhance our ability to create more effective vaccines and establish tools to selectively enhance or inhibit the formation of plasma or memory cells in vivo.
|Kaminski, Denise A; Lee, Byung O; Eaton, Sheri M et al. (2009) CD28 and inducible costimulator (ICOS) signalling can sustain CD154 expression on activated T cells. Immunology 127:373-85|
|Partida-Sanchez, Santiago; Goodrich, Stephen; Kusser, Kim et al. (2004) Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact on the development of humoral immunity. Immunity 20:279-91|