Natural helper (NH) cells are recently discovered innate immune cells that confer protective type 2 immunity during helminth infection and mediate influenza-induced airway hypersensitivity. Little is known about the ontogeny of NH cells. We report in this study that NH cells derive from bone marrow lymphoid progenitors. Using RAG-1Cre/ROSA26(YFP) mice, we show that most NH cells are marked with a history of RAG-1 expression, implying lymphoid developmental origin. The development of NH cells depends on the cytokine receptor Flt3, which is required for the efficient generation of bone marrow lymphoid progenitors. Finally, we demonstrate that lymphoid progenitors, but not myeloid-erythroid progenitors, give rise to NH cells in vivo. This work therefore expands the lymphocyte family, currently comprising T, B, and NK cells, to include NH cells as another type of innate lymphocyte that derives from bone marrow lymphoid progenitors.
