Retinoic-Acid-Receptor-Related Orphan Nuclear Receptor Alpha Is Required for Natural Helper Cell Development and Allergic Inflammation

Natural helper (NH) cells are innate lymphoid cells (ILCs) that produce T helper-2 (Th2)-cell-type cytokines in the lung- and gut-associated lymphoid tissues. Currently, the lineage relationship between NH cells in different tissues and between NH cells and interleukin-22 (IL-22)-producing retinoic-acid-receptor-related orphan receptor (ROR)gamma t-positive ILCs is unclear. Here, we report that NH cells express ROR alpha, but not ROR gamma t. ROR alpha-deficient, but not ROR gamma t-deficient, mice lacked NH cells in all tissues, whereas all other lymphocytes, including ROR gamma t(+) ILCs, were unaffected. NH-cell-deficient mice generated by ROR alpha-deficient bone-marrow transplantation had normal Th2 cell responses but failed to develop acute lung inflammation in response to protease allergen, thus confirming the essential role of NH cells in allergic lung inflammation. We have also identified ROR alpha-dependent NH cell progenitors in the bone marrow. Thus, all NH cells belong to a unique ROR alpha-dependent cell lineage separate from other lymphoid cell lineages.