Volume 20, No 6, Jun 2010

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 20 Issue 6, June 2010: 631-646

ORIGINAL ARTICLES

Requirement for cyclin D3 in germinal center formation and function

Jonathan U Peled¹, J Jessica Yu¹, Jeganathan Venkatesh², Enguang Bi¹, B Belinda Ding^1,5, Melissa Krupski-Downs¹, Rita Shaknovich³, Piotr Sicinski⁴, Betty Diamond², Matthew D Scharff¹ and B Hilda Ye¹

¹Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA

²The Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA

³Departments of Medicine and Pathology, Weill Cornell College of Medicine, New York, NY 10021, USA

⁴Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA

⁵Current address: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA Correspondence: B Hilda Ye,(hilda.ye@einstein.yu.edu)

Germinal centers (GC) of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antibody genes. Although it is generally believed that GC B cells employ a unique proliferative program to accommodate these processes, little is known about how the GC-associated cell cycle is orchestrated. The D-type cyclins constitute an important component of the cell cycle engine that enables the cells to respond to physiological changes. Cell type- and developmental stage-specific roles of D-type cyclins have been described but the cyclin D requirement during GC reaction has not been addressed. In this study, we report that cyclin D3 is largely dispensable for proliferation and Ig class switching of in vitro activated B cells. In contrast, GC development in Ccnd3^−/− mice is markedly impaired, as is the T cell-dependent antibody response. Within the GC, although both switched and unswitched B cells are affected by cyclin D3 inactivation, the IgM⁻ pool is more severely reduced. Interestingly, despite a compensatory increase in cyclin D2 expression, a significant number of Ccnd3^−/− GC B cells accumulate in quiescent G0 state. Lastly, although cyclin D3 inactivation did not disrupt BCL6 expression in GC B cells, it completely blocked the GC promoting effect of BCL6 overexpression, suggesting that cyclin D3 acts downstream of BCL6 to regulate GC formation. This is the first demonstration that cyclin D3 plays an important and unique role at the GC stage of B cell development.

Cell Research (2010) 20:631-646. doi:10.1038/cr.2010.55; published online 20 April 2010

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