Abstract
Growing evidence indicate that large antigen-containing particles induce potent T cell-dependent high-affinity antibody responses. These responses require large particle internalization after recognition by the B cell receptor (BCR) on B cells. However, the molecular mechanisms governing BCR-mediated internalization remain unclear. Here we use a high-throughput quantitative image analysis approach to discriminate between B cell particle binding and internalization. We systematically show, using small molecule inhibitors, that human B cells require a SYK-dependent IgM-BCR signaling transduction via PI3K to efficiently internalize large anti-IgM-coated particles. IgM-BCR-mediated activation of PI3K involves both the adaptor protein NCK and the co-receptor CD19. Interestingly, we here reveal a strong NCK-dependence without profound requirement of the co-receptor CD19 in B cell responses to large particles. Furthermore, we demonstrate that the IgM-BCR/NCK signaling event facilitates RAC1 activation to promote actin cytoskeleton remodeling necessary for particle engulfment. Thus, we establish NCK/PI3K/RAC1 as an attractive IgM-BCR signaling axis for biological intervention to prevent undesired antibody responses to large particles.
Highlights
The first step in induction of antibody production is binding of external antigen to the B cell receptor (BCR) on naive B cells
We aimed to identify the molecular mechanisms that govern internalization of large particles and bacteria by human B cells, as this process enables B cells that recognize one antigen to attract broad T cell help directed against other antigens in the particle, and yields broad undesired antibody responses in autoimmunity and blood transfusion
We present data that demonstrate that human B cells take up large particles via the IgM-BCR-induced NCK/phosphoinositide-3 kinase (PI3K)/RAC1 axis to drive actin cytoskeleton modulation, without a requirement for the co-receptor CD19 (Figure 6)
Summary
The first step in induction of antibody production is binding of external antigen to the B cell receptor (BCR) on naive B cells. BCR ligation by antigen results in BCR-mediated transmembrane signaling and antigen internalization, followed by proteolytic degradation and presentation of antigen-derived peptides through major histocompatibility complex class II (MHCII) molecules on the B cell plasma membrane [1,2,3]. MHCII/antigen complexes are recognized by antigen-specific T cell receptors expressed by CD4+ T cells [4]. After formation of a stable antigen-specific interaction, B cells receive help from CD4+ T cells via co-stimulatory molecules and soluble cytokines to promote B cell differentiation into high-affinity antibody-producing plasma cells during germinal center (GC) reactions in secondary lymphoid organs. Phosphorylation of the ITAMs is initiated by the SRC family
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