Mature B cells and mesenchymal stem cells control emergency myelopoiesis

Abstract

Systemic inflammation halts lymphopoiesis and prioritizes my-eloid cell production. How blood cell production switches from homeostasis to emergency myelopoiesis is incompletely un-derstood. Here, we show that lymphotoxin-beta receptor (LT beta R) signaling in combination with TNF and IL-1 receptor signaling in bone marrow mesenchymal stem cells (MSCs) down-regulates Il7 expression to shut down lymphopoiesis during systemic inflammation. LT beta R signaling in MSCs also promoted CCL2 production during systemic inflammation. Pharmacological or genetic blocking of LT beta R signaling in MSCs partially enabled lymphopoiesis and reduced monocyte numbers in the spleen during systemic inflammation, which correlated with reduced survival during systemic bacterial and viral infections. Inter-estingly, lymphotoxin-alpha 1 beta 2 delivered by B-lineage cells, and specifically by mature B cells, contributed to promote Il7 down -regulation and reduce MSC lymphopoietic activity. Our studies revealed an unexpected role of LT beta R signaling in MSCs and identified recirculating mature B cells as an important regulator of emergency myelopoiesis.