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Restriction of memory B cell differentiation at the germinal center B cell positive selection stage.

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posted on 22.05.2020 by Amparo Toboso-Navasa, Arief Gunawan, Giulia Morlino, Rinako Nakagawa, Andrea Taddei, Djamil Damry, Yash Patel, Probir Chakravarty, Martin Janz, George Kassiotis, Robert Brink, Martin Eilers, Dinis Pedro Calado
Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.

Funding

Crick (Grant ID: 10057, Grant title: Calado FC001057) Crick (Grant ID: 10099, Grant title: Kassiotis FC001099) Medical Research Council (Grant ID: MR/J008060/1, Grant title: MRC MR/J008060/1)

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