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

Amparo Toboso-Navasa,George Kassiotis,Dinis Pedro Calado,Martin Eilers,Andrea Taddei,Probir Chakravarty,Rinako Nakagawa,Djamil Damry,Yash Patel,Giulia Morlino,Martin Janz,Arief Gunawan,Robert Brink

doi:10.1084/jem.20191933

Abstract

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.

Highlights

The germinal center (GC) is an antigen- and T cell–dependent reaction in which B cells undergo affinity maturation and differentiation (De Silva and Klein, 2015; Victora and Nussenzweig, 2012)
Complexes formed by MYC and MIZ1 in these cells were required for repression of MIZ1 target genes, effective cell cycle engagement of light zone (LZ) B cells, GC expansion, and plasma cell (PC) formation
Most of the MIZ1 target genes repressed by MYC–MIZ1 complexes were enriched in memory B cells (MBCs), and the absence of MYC–MIZ1 complexes increased

Summary

Introduction

The germinal center (GC) is an antigen- and T cell–dependent reaction in which B cells undergo affinity maturation and differentiation (De Silva and Klein, 2015; Victora and Nussenzweig, 2012). That MBCs have, in general, lower antigen affinity compared with LZ B cells fated for GC expansion and PC differentiation (De Silva and Klein, 2015; Shinnakasu et al, 2016; Weisel et al, 2016). MYC is critically required for cell cycle entry of LZ MYC+ cells, and these cells are primarily fated for GC expansion and PC differentiation (Calado et al, 2012; Dominguez-Sola et al, 2012; Ise et al, 2018). We raised the question whether MYC activity in LZ MYC+ cells restricts MBC differentiation

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Conclusion