How TLR9 Signaling shapes the survival, differentiation and the metabolism of B cells

Abstract

Abstract The signaling cascades initiated by binding of the antigen to B cell receptor (BCR) leads to rapid increases in cellular respiration, nutrient uptake and expression of various activation markers. However, unless a second, independent stimulus is received soon after antigen binding, BCR signaling does not lead to B cell proliferation and differentiation. Instead, BCR signaling alone leads to a dysregulation of cellular calcium homeostasis which in turn causes mitochondrial dysfunction and a phenomenon called activation induced cell death. The second signal can be provided by Toll like receptor (TLR) signaling, indicating the presence of an acute infection or through B cell-T cell interactions that rules out that the initial antigen was a prohibited self-antigen. Additionally, there is an interplay between TLR versus T cell mediated second signals, namely that TLR signaling trumped the need for the antigen-stimulated B cell to interact with T cells to receive a ‘go’ signal. TLR stimulation decreased B cells’ ability to capture, process and present antigens to solicit help from T cells. Rather TLRs directly boosted B cell antibody and cytokine secretion and proliferation. Thus, TLR signals drive B cells toward rapid T cell-independent differentiation to plasma cells providing rapid neutralizing antibody production to fight off infections quickly. In contrast B cells that receive their survival signals from T cells are induced to undergo a time-consuming process that is necessary for antibody affinity maturation and long-lasting immune memory. Therefore, the TLR driven shortcut to quick antibody comes with a price which is the absence of “crème de la crème” antibodies that would protect the body from subsequent infections for years to come.