Innate lymphoid cells facilitate NK cell development through a lymphotoxin-mediated stromal microenvironment

Abstract

Natural killer (NK) cell development relies on signals provided from the bone marrow (BM) microenvironment. It is thought that lymphotoxin (LT) alpha(1)beta(2) expressed by the NK cell lineage interacts with BM stromal cells to promote NK cell development. However, we now report that a small number of ROR gamma t(+) innate lymphoid cells (ILCs), and not CD3(-)NK1.1(+) cells, express LT to drive NK development. Similar to LT-/- or ROR gamma t(-/-) mice, the mice conditionally lacking LT alpha(1)beta(2) on ROR gamma t(+) ILCs experience a developmental arrest at the immature NK stages, between stages of NK development to the mature NK cell stage. This developmental block results in a functional deficiency in the clearance of NK-sensitive tumor cells. Reconstitution of Thy1(+) ILCs from BM or purified ROR gamma t(+) ILCs from lamina propria lymphocytes into LT-deficient ROR gamma t(+) BM cultures rescues NK cell development. These data highlight a previously undiscovered role of ROR gamma t(+) ILCs for NK cell development and define LT from ILCs as an essential molecule for the stromal microenvironment supporting NK cell development.