The ability of the immune system to provide protection from recurrent infection is highly dependent upon antigen (Ag)-specific secondary, or memory, responses. Despite the critical nature of secondary responses, we know little about the interactions and signaling events that produce such a remarkable result. The overall goal of this proposal is to better understand the cellular interactions that drive secondary Ab responses in vivo. While memory B cells are typically accredited with the rapid rise in Ag-specific antibody titers seen following secondary immune responses, the contribution of naive B cells to the secondary response is unclear. Our central hypothesis postulates that dendritic cell-mediated B cell activation upon secondary Ag challenge is critical to the rapid nature and diversity of secondary Ab responses. By employing an adoptive transfer system using naive Ag-specific B cells from mice carrying a targeted Ig heavy chain specific for the hapten (4-hydroxy-3-nitropheny)acetyl (NP), we will characterize in Aim 1 the response of naive B cells during secondary (recall) Ag responses, and determine the requirements for their activation including B cell receptor (BCR) affinity for Ag, CD4 T cell help, and CD22 expression. Immunization with immune complexes enhances primary Ab responses through an unknown mechanism that requires Fc? receptors on bone marrow-derived cells, possibly DCs. DCs have recently been shown to internalize and present Ag directly to B cells, inducing their activation.
In Aim 2, we will determine which subsets of splenic DCs normally found in vivo can support B cell activation and differentiation using an Ag- specific DC-B cell co-culture system developed in our lab. We will further extend these studies to determine whether DCs are required for naive B cell activation during secondary Ab responses, and test the hypothesis that immunization with Ag-bearing DCs is sufficient to produce the rapid and/or diverse B cell responses that are characteristic of secondary Ab responses found in situ. The majority of vaccines in use today rely upon the generation of strong and long-lasting antibody responses. Understanding the mechanisms that lead to protective Ab responses are critical for the rational design of vaccines aimed at stimulating the humoral arm of the immune system to produce neutralizing Ab. The studies in this proposal will contribute to our knowledge of B cell responses following secondary (or booster) immunizations, a strategy often employed by vaccination regimens to raise high levels of serum Ab
|Chappell, Craig P; Draves, Kevin E; Giltiay, Natalia V et al. (2012) Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med 209:1825-40|