Open AccessCyclin D3 drives inertial cell cycling in dark zone germinal center B cells
Author(s) -
Juhee Pae,
Jonatan Ersching,
Tiago B. R. Castro,
Marta Schips,
Luka Mesin,
Samuel J. Allon,
José Ordovás-Montañés,
Coraline Mlynarczyk,
Ari Melnick,
Alejo Efeyan,
Alex K. Shalek,
Michael MeyerHermann,
Gabriel D. Victora
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201699
Subject(s) - germinal center , somatic hypermutation , cyclin d3 , biology , cell cycle , cyclin d2 , cyclin , microbiology and biotechnology , cyclin d1 , cell growth , cyclin b , cyclin d , b cell , cancer research , cell , immunology , genetics , antibody
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.