Monovalent and Multivalent Ligation of the B Cell Receptor Exhibit Differential Dependence upon Syk and Src Family Kinases

The extent of receptor clustering determines which kinases mediate B cell receptor signaling. Crowd-Sourced Signaling Unlike T cells, B cells respond to soluble antigens, which can either be monomeric or multimeric, the latter of which induce clustering of the B cell receptor (BCR). Antigen-mediated stimulation of T and B cells involves two distinct sets of tyrosine kinases: the Src family kinases (SFKs) and the Syk family. To understand how these two kinase families contribute to B cell activation, Mukherjee et al. mathematically modeled the contributions of SFKs and Syk to BCR signaling and verified their findings in cells. In response to soluble multimeric, BCR-clustering antigens, Syk was sufficient to mediate B cell activation, albeit with slow kinetics. However, in response to soluble monomeric antigens, which failed to induce BCR clustering, both families of kinases were required. Together, these data suggest that SFKs increase the sensitivity of B cells to monomeric antigens and ensure B cell activation. The Src and Syk families of kinases are two distinct sets of kinases that play critical roles in initiating membrane-proximal B cell receptor (BCR) signaling. However, unlike in other lymphocytes, such as T cells, the “division of labor” between Src family kinases (SFKs) and Syk in B cells is not well separated because both Syk and SFKs can phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) present in proteins comprising the BCR. To understand why B cells require both SFKs and Syk for activation, we investigated the roles of both families of kinases in BCR signaling with computational modeling and in vitro experiments. Our computational model suggested that positive feedback enabled Syk to substantially compensate for the absence of SFKs when spatial clustering of BCRs was induced by multimeric ligands. We confirmed this prediction experimentally. In contrast, when B cells were stimulated by monomeric ligands that failed to produce BCR clustering, both Syk and SFKs were required for complete and rapid BCR activation. Our data suggest that SFKs could play a pivotal role in increasing BCR sensitivity to monomeric antigens of pathogens and in mediating a rapid response to soluble multimeric antigens of pathogens that can induce spatial BCR clustering.