Mature B cells and mesenchymal stem cells control emergency myelopoiesis.

Systemic inflammation halts lymphopoiesis and prioritizes myeloid cell production. How blood cell production switches from homeostasis to emergency myelopoiesis is incompletely understood. Here, we show that lymphotoxin-ß receptor (LTßR) 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. LTßR signaling in MSCs also promoted CCL2 production during systemic inflammation. Pharmacological or genetic blocking of LTßR 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. Interestingly, lymphotoxin-α1ß2 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 LTßR signaling in MSCs and identified recirculating mature B cells as an important regulator of emergency myelopoiesis.

Allogeneic TCRαß deficient CAR T-cells targeting CD123 in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCRαßneg T cells generated from healthy donors using TALEN® gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML.