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Natural helper cell development and their role in mediating the innate Th2 inflammatory response

University of British Columbia

Overproduction of cytokines by T helper 2 (Th2) cells in the lung is thought to be a cause of allergic lung inflammation. We found that innate lymphocytes termed lung Natural Helper cells are a T cell-independent source of Th2 cytokines in allergen stimulated lungs. When stimulated by IL-33 plus IL-2, IL-7 or thymic stroma lymphopoietin, lung Natural Helper cells (identified as Lineage⁻Sca-1⁺c-Kitlow⁻CD25⁺CD127⁺) produced large amounts of IL-5 and IL-13. Intranasal administration of the protease allergen, papain, or house dust mite extract induced eosinophilic infiltration and mucus hyper-production in the lungs of wild-type and Rag1⁻/⁻ mice, but not Rag2⁻/⁻Il2rg⁻/⁻ mice that lack lung Natural Helper cells. Lung Natural Helper cell depletion inhibited papain-induced airway inflammation in Rag1⁻/⁻ mice, whereas adoptive transfer of lung Natural Helper cells enabled Rag2⁻/⁻Il2rg⁻/⁻ mice to respond. Treatment of lung explants with papain induced IL-33 and thymic stroma lymphopoietin production by stroma cells and IL-5 and IL-13 production by lung Natural Helper cells. We also examined the lineage relationship between Natural Helper cells in different tissues and IL-22 producing retinoid receptor related orphan receptor (ROR)γt-positive innate lymphoid cells. We found that Natural Helper cells expressed RORα but not RORγt. RORα deficient, but not RORγt-deficient, mice lacked Natural Helper cells in all tissues while all other lymphocytes including RORγt⁺ innate lymphocytes were unaffected. Natural Helper cell deficient mice generated by RORα-deficient bone marrow transplantation had a normal Th2 cell response but failed to develop acute allergic lung inflammation in response to protease allergen. We also identified RORα-dependent Natural Helper cell progenitors that were distinct from common lymphoid progenitors in the bone marrow. Thus, these results showed that all Natural Helper cells belong to a distinct cell lineage separate from other lymphoid lineages and they are critical for protease allergen-induced airway inflammation.

Text

2013-01-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/43861

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/