During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by “inertia.” We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma–associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells
Dr. Ersching died in October 2020.
Disclosures: A. Melnick reports grants from Janssen, Sanofi, and Daiichi Sankyo, and personal fees from KDAC, Epizyme, Constellation, Jubilant, and ExoTherapeutics outside the submitted work. J. Ordovas-Montanes reports personal fees from Cellarity outside the submitted work. No other disclosures were reported.
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Juhee Pae, Jonatan Ersching, Tiago B.R. Castro, Marta Schips, Luka Mesin, Samuel J. Allon, Jose Ordovas-Montanes, Coraline Mlynarczyk, Ari Melnick, Alejo Efeyan, Alex K. Shalek, Michael Meyer-Hermann, Gabriel D. Victora; Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells. J Exp Med 5 April 2021; 218 (4): e20201699. doi: https://doi.org/10.1084/jem.20201699
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