Submitted November 10, 2008
Accepted March 19, 2009
Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes
Teresita L. Arenzana, Matthew R. Smith-Raska, and Boris Reizis*
Department of Microbiology, Columbia University Medical Center, New York, NY, United States
* Corresponding author; email: bvr2101{at}columbia.edu.
The development, homeostasis and function of B lymphocytes involve multiple rounds of B cell receptor (BCR)-controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of hematopoietic stem cell maintenance, in B cell development and homeostasis. Pan-hematopoietic or B cell-specific deletion of Zfx in the bone marrow blocked B cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response, and delayed induction of Cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B cell lineage, and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.
