Adult hematopoietic stem cells (HSCs) are maintained in bone marrow (BM) and give rise to all blood cell types. The maintenance and the differentiation of blood cells including immune cells are essential for host defense. Cells involved in bone homeostasis share microenvironments with HSCs in BM and contribute to hematopoiesis under physiological conditions, but bone cell function in acute immune reactions has been poorly understood. Sepsis is the acute host inflammatory response to severe infection associated with high mortality, which is often caused by the immunosuppression mediated by lymphocyte apoptosis. However, it is unknown how lymphopenia persists after the accelerated lymphocyte apoptosis. Here we show that sepsis rapidly suppressed osteoblastic bone formation and reduced the number of common lymphoid progenitors (CLPs) in the BM as well as the peripheral T and B cell numbers, suggesting the role of osteoblasts in the regulation of CLPs. To investigate the precise role of osteoblasts in the regulation of CLPs, we generated osteoblast-ablated mice by mating Osterix (Osx)-Cre mice with puΔtk mice. In these mice, Cre-expressing cells can be ablated by ganciclovir administration. Similar to sepsis, transient ablation of osteoblasts led to a marked decrease in the CLP number. IL-7, which is important for maintaining lymphocytes, in BM was decreased during sepsis. Osteoblast-specific IL-7 conditional knock-out (cKO) mice were generated by crossing Il7flox/flox mice with Osx-Cre or Osteocalcin-Cre. These cKO mice exhibited the lymphopenic phenotype together with a lower CLP number, indicating that osteoblast-derived IL-7 supports CLPs in the BM. Activation of osteoblasts by intermittent parathyroid hormone treatment improves sepsis-induced lymphopenia. The survival rate for sepsis was decreased in osteoblast-ablated mice. This study demonstrated that IL-7 derived from osteoblasts regulates lymphocyte differentiation in the acute immune reaction, indicating that bone cells serve as a novel therapeutic target of life-threatening process in the immune reactions.