The concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21

Dimitra Zotos,Philip D Hodgkin,Andrey Kan,Gordon K Smyth,David M Tarlinton,Craig I Mckenzie,Marcus J Robinson,Isaak Quast,Connie S N Li-Wai-Suen

doi:10.1038/s41467-021-27477-0

Abstract

Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ. Cell cycle progression of DZ B cells is unaffected by IL-21 availability, as is the zone phenotype of the most highly proliferative GC B cells. Collectively, this study characterises the development of GC zones as a function of time and B cell proliferation and identifies IL-21 as an important regulator of these processes. These data help explain the requirement for IL-21 in normal antibody affinity maturation.

Highlights

Humoral immune responses require germinal centres (GC) for antibody affinity maturation
By quantifying GC zone development in conjunction with cell cycle phases during the first week of a TD response, we have determined that IL-21 functions to set the ratio of light zone (LZ) to dark zone (DZ) cells and to promote the entry of antigen-specific LZ B cells into DNA synthesis
We have mapped the distribution of the phases of the cell cycle within GC zones and determined gene expression differences in GC B cells arising from an absence of IL-21

Summary

Introduction

Humoral immune responses require germinal centres (GC) for antibody affinity maturation. GC are established by rapid B cell proliferation, followed by the development of two distinct zones, which is essential for efficient affinity maturation and maintenance of the GC1,2,6 One of these zones, the light zone (LZ), is comprised of centrocytes (CC), centered on CXCL13-secreting follicular dendritic cells (FDC) and enriched for the CD4 T follicular helper (Tfh) cells that are absolutely required for GC function. We conclude that IL-21 promotes proliferation through entry into the S phase and functions to limit B cell time out of cell cycle This action is required to establish a normal GC zone distribution and we propose this controls the duration of the reaction, the extent of affinity maturation, and the quality of GC output

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Results

Conclusion