Antibody (Ab)-producing B cells (plasma cells or PCs) provide crucial protection against viral infections and are involved in the clearance of many viral pathogens including influenza A virus. Furthermore, the vast majority of the current anti-viral vaccines are effective because the vaccines induce neutralizing Abs by the PCs. Despite the importance of these PCs in protection against virus infections, we know little about how virus-specific B cells are induced following infection or how these B cells are selected into the long-lived PC (LL-PC) and memory B cell (Bmem) subsets to provide protection following re-exposure to the same pathogen. Unfortunately, this means that we cannot empirically design new vaccines that induce lasting, protective humeral immunity to viruses. In fact, we still do not understand why some anti-viral vaccines confer life-long protection while others are only effective for a short time. Therefore, the goal of this proposal is to identify the key molecular and cellular signals that initiate the development of virus-specific LL-PCs. We recently identified a novel virus-induced T-bet and IFNy-dependent signaling pathway in B cells that is required for the development of bone marrow resident LL-PCs following flu infection. Interestingly, T-bet or IFNyR deficient B cells are selectivley retained within the germinal center microenvironment and remain for months, suggesting that T-bet and IFNy-dependent signals regulate the cell fate decisions in the germinal center that control whether a virus-specific B cell will be eliminated from the repertoire or selected into the LL-PC or Bmem subsets. The objectives of this proposal are to determine whether: (i) the balance between the T-box transcription factors, T-bet and Eomes, differentially affects the development of LL-PC and Bmem cells from the germinal center B cell precursor (ii) all viral infections induce the T-bet/Eomes dependent cell fate decisions for germinal center B cells and (iii) whether the IFNg/T-bet signaling pathway is actively engaged in human B cells responding to viral infection or anti-viral vaccination. Together, these experiments will increase our understanding of how lasting humoral immunity to viruses is generated and maintained and will improve our ability to design more effective vaccines against a range of pathogenic viruses.
Virus-specific neutralizing antibodies (Abs) are critical for protection from natural infection with many viruses including the flu virus and most current vaccines work by eliciting Abs. However, some virus vaccines are much more effective than others and we do not understand why this is so. Experiments in this proposal are designed to determine how the immune system normally responds to viruses by making Abs and to develop strategies that are more effective in inducing this protective and lasting response.
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