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)γt-positive ILCs is unclear. Here, we report that NH cells express RORα, but not RORγt. RORα-deficient, but not RORγt-deficient, mice lacked NH cells in all tissues, whereas all other lymphocytes, including RORγt(+) ILCs, were unaffected. NH-cell-deficient mice generated by RORα-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 RORα-dependent NH cell progenitors in the bone marrow. Thus, all NH cells belong to a unique RORα-dependent cell lineage separate from other lymphoid cell lineages.
Natural Helper (NH) cells are Th2 cytokine-producing innate lymphoid cells (ILCs) in, or associated with the mucosal tissues of the lung and gut. Currently, the lineage relationship between NH cells in different tissues and between NH cells and interleukin-22 (IL-22)-producing retinoid receptor-related orphan receptor (ROR)γt-positive ILCs is unclear. Here, we report that NH cells express RORα but not RORγt. RORα-deficient, but not RORγt-deficient, mice lack NH cells in the lung, small and large intestines while all other lymphocytes including RORγt+ ILCs are unaffected. We have also identified RORα-dependent Lin-Sca-1hic-kit-CD127+CD25+ NH cell progenitors different from common lymphoid progenitors in the bone marrow. The putative NH cell progenitors transplanted into NOD/SCID/Il2rg-/- mice develop into NH cells but not other lymphocytes including RORγt+ ILCs. Thus, all NH cells belong to a distinct cell lineage separate from other lymphoid cell lineages. NH cell-deficient mice generated by RORα-deficient bone marrow transplantation into lymphodeficient Rag2-/-Il2rg-/- mice have normal Th2 cell response but fail to develop acute allergic lung inflammation in response to protease allergens. NH cell-deficient mice further reveal the role of NH cells in allergic lung inflammation.
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