Lung Natural Helper Cells Are a Critical Source of Th2 Cell-Type Cytokines in Protease Allergen-Induced Airway Inflammation

Abstract

Overproduction of cytokines by T helper 2 (Th2) cells in the lung is thought to be a cause of asthma. Here we report that innate lymphocytes termed lung natural helper (LNH) cells are a T cell-independent source of Th2 cell-type cytokines in protease allergen-treated lungs. LNH (Lin(-)Sca-1(+)c-kit(+/lo)CD25(+)CD127(+)) cells, when stimulated by IL-33 plus IL-2, IL-7, or thymic stroma lymphopoietin (TSLP), produced large amounts of IL-5 and IL-13. Intranasal administration of protease allergen papain induced eosinophil infiltration and mucus hyperproduction in the lung of wild-type and Rag1(-/-) mice, but not in Rag2(-/-)Il2rg(-/-) mice that lack LNH cells. LNH cell depletion inhibited papain-induced airway inflammation in Rag1(-/-) mice whereas adoptive transfer of LNH cells enabled Rag2(-/-)Il2rg(-/-) mice to respond to papain. Treatment of lung explants with papain induced IL-33 and TSLP production by stroma cells and IL-5 and IL-13 production by LNH cells. Thus, LNH cells are critical for protease allergen-induced airway inflammation.

Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation

“…One previous study reported that lung NH cells require IL-2, IL-7 or TSLP for IL-33-induced proliferation 15 . The difference between their data and ours may be due to the different protocols employed for the isolation of lung NH cells; we used a combination of antibodies against Thy1, c-Kit and Sca-1, whereas the previous study used antibodies against Sca-1, c-Kit, IL-7R and CD25.…”

“…As shown here, the inhibition of TSLP or its key signalling molecule, STAT5, can restore the sensitivity of NH cells to corticosteroids. After we first reported NH cells in the FALC 10 , several groups have demonstrated the presence of similar group 2 ILCs in the lung and variously designated these cells as lung NH cells 15 , Lin À CD25 þ CD44 hi lymphoid cells 33 or pulmonary ILC 16 . These lung-derived NH cells are present in Rag1 À / À mice, but deficient in Il7 À / À or Rag2 À / À Il2rg À / À mice 15,33 as are FALC NH cells 10 .…”

“…NH cells can produce large amounts of type-2 cytokines such as IL-5 and IL-13 in response to IL-33. Several groups have characterized populations of type-2 cytokine-producing ILCs associated with IL-33 mediate diseases in the lung [15][16][17][18][19][20][21] . However, it is unknown whether NH cells are involved in the observed corticosteroid sensitivity.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…ILC2s produce IL‐5 and IL‐13 in response to epithelial cell‐derived IL33 and/or IL‐25 18, 19, 20. Their production of IL‐13 is critical for helminth expulsion,18, 20, 21 while they can also drive atopic dermatitis and allergic inflammations 22, 23. ILC3s in turn are characterized by their innate ability to secrete IL‐17A, IL‐17F, IL‐22 and GM‐CSF 4, 24.…”

Enforced Expression of Gata3 in T Cells and Group 2 Innate Lymphoid Cells Increases Susceptibility to Allergic Airway Inflammation in Mice

“…Because of their Th2 cytokine profile, they have been named group 2 ILCs (ILC2) and can be identified as lineage-negative cells expressing receptors for IL-2, IL-7, and IL-33 (4). The involvement of ILC2 in asthma was recently demonstrated in various mouse models, including HDM-driven allergic AAI (5)(6)(7)(8). ILC2 have also been identified in human lung and are associated with chronic rhinosinusitis (9)(10)(11).…”