Kläsener, Kathrin ; Jellusova, Julia ; Andrieux, Geoffroy ; Salzer, Ulrich ; Böhler, Chiara ; Steiner, Sebastian N. ; Albinus, Jonas B. ; Cavallari, Marco ; Suess, Beatrix ; Voll, Reinhard E. ; Boerries, Melanie ; Wollscheid, Bernd ; Reth, Michael (2021):
CD20 as a gatekeeper of the resting state of human B cells.
In: Proceedings of the National Academy of Sciences of the United States of America, 118 (7), pp. e2021342118. ISSN 1091-6490,
DOI: 10.1073/pnas.2021342118,
[Article]

Abstract

CD20 is a B cell-specific membrane protein and represents an attractive target for therapeutic antibodies. Despite widespread usage of anti-CD20 antibodies for B cell depletion therapies, the biological function of their target remains unclear. Here, we demonstrate that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. CRISPR/Cas9-mediated ablation of CD20 in resting B cells resulted in relocalization and interaction of the IgM-class B cell antigen receptor with the coreceptor CD19. This receptor rearrangement led to a transient activation of B cells, accompanied by the internalization of many B cell surface marker proteins. Reexpression of CD20 restored the expression of the B cell surface proteins and the resting state of Ramos B cells. Similarly, treatment of Ramos or naive human B cells with the anti-CD20 antibody rituximab induced nanoscale receptor rearrangements and transient B cell activation in vitro and in vivo. A departure from the resting B cell state followed by the loss of B cell identity of CD20-deficient Ramos B cells was accompanied by a PAX5 to BLIMP-1 transcriptional switch, metabolic reprogramming toward oxidative phosphorylation, and a shift toward plasma cell development. Thus, anti-CD20 engagement or the loss of CD20 disrupts membrane organization, profoundly altering the fate of human B cells.

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