The transcription factor Zfx regulates lymphocyte development and homeostasis
The development, maintenance, and function of lymphocytes involve multiple rounds of antigen (Ag) receptor-induced proliferation followed by prolonged survival in the quiescent state. We tested the role of the transcription factor Zfx, a recently identified regulator of stem cell survival, in lymphocyte development and homeostasis. Conditional Zfx deletion in the T cell lineage resulted in a partial block at the double-negative to double-positive transition in thymocyte development and led to the impaired survival of naïve T cells in the periphery. Ablation of Zfx in the B cell lineage blocked the pre-BI/pre-BII cell transition in the bone marrow and impaired the generation of the B-1 B cell lineage. Zfx-deficient peripheral B cells showed accelerated turnover, depletion of mature recirculating B cells, reduced germinal center formation, and delayed antibody responses. The loss of Zfx did not affect BCR-mediated proximal signaling, yet impaired BCR-induced proliferation and survival. Genome-wide expression analysis revealed the aberrant induction of the integrated stress response in BCR-activated Zfx-deficient B cells. These data suggest that Zfx controls both Ag receptor-induced proliferation and peripheral homeostasis of mature lymphocytes. In mature B cells, this is achieved at least in part by restraining the stress response following BCR signaling.