Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells
Alessandro Camponeschi, Kathrin Kläsener, Timothy Sundell, Christina Lundqvist, Paul T. Manna, Negar Ayoubzadeh, Martina Sundqvist, Katrin Thorarinsdottir, Mariele Gatto, Marcella Visentini, Karin Önnheim, Alaitz Aranburu, Huamei Forsman, Olov Ekwall, Linda Fogelstrand, Inger Gjertsson, Michael Reth, Inga‐Lill Mårtensson
Abstract
CD38 is a multifunctional protein expressed on the surface of B cells in healthy individuals but also in B cell malignancies. Previous studies have suggested a connection between CD38 and components of the IgM class B cell antigen receptor (IgM-BCR) and its coreceptor complex. Here, we provide evidence that CD38 is closely associated with CD19 in resting B cells and with the IgM-BCR upon engagement. We show that targeting CD38 with an antibody, or removing this molecule with CRISPR/Cas9, inhibits the association of CD19 with the IgM-BCR, impairing BCR signaling in normal and malignant B cells. Together, our data suggest that CD38 is a new member of the BCR coreceptor complex, where it exerts a modulatory effect on B cell activation upon antigen recognition by regulating CD19. Our study also reveals a new mechanism where α-CD38 antibodies could be a valuable option in therapeutic approaches to B cell malignancies driven by aberrant BCR signaling.