Lead Impairs the Development of Innate Lymphoid Cells by Impeding the Differentiation of Their Progenitors

Abstract Lead (Pb) is a heavy metal toxic to the immune system, yet the influence of Pb on innate lymphoid cells (ILC) remains to be defined. In this study, we found that occupationally relevant level of Pb exposure impaired ILC development at the progenitor level by activating Janus Kinase1. C57BL/6 mice treated with 1250 ppm, but not 125 ppm Pb acetic via drinking water for 8 weeks had reduced number of mature ILC, which was not caused by increased apoptosis or suppressed proliferation. Conversely, Pb increased the number of innate lymphoid cell progenitors (ILCP) in the bone marrow. The discordant observation indicated that an obstruction of ILCP differentiation into mature ILC during Pb exposure existed. Pb directly acted on ILCP to suppress their proliferation, indicating that ILCP were less activated during Pb exposure. Reciprocal ILCP transplantation assay confirmed that Pb impeded the differentiation of ILCP into mature ILC, as ILCP gave rise to fewer mature ILC in Pb-treated recipients compared with control recipients. In vitro assays suggested that the obstruction of ILCP differentiation by Pb exposure was due to increased activation of Janus Kinase1. Thus, Pb impeded ILCP differentiation into mature ILC to result in an accumulation of ILCP in the bone marrow and the resultant decreased number of mature ILC in lymphoid and nonlymphoid tissues in mice. Moreover, by analyses of ILC and ILCP in peripheral blood mononuclear cells of human subjects occupationally exposed to Pb, we revealed that Pb might also impede the development of ILC in human.