ICOS protects against mortality from acute lung injury through activation of IL-5+ ILC2s

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. IPF Patients suffer from a high rate of pulmonary infections and acute exacerbations of disease that further contribute to pulmonary decline. Low expression of the inducible T-cell costimulatory molecule (ICOS) in peripheral blood mononuclear cells predicts decreased survival of IPF patients, but the mechanisms by which ICOS protects are unclear. Using a model of bleomycin-induced lung injury and fibrosis, we now demonstrate that ICOS expression enhances survival from lung injury rather than regulating fibrogenesis. Of ICOS expressing cells, type 2 innate lymphocytes (ILC2s) are the first to respond to bleomycin-induced injury, and this expansion is ICOS-dependent. Interestingly, a similar decrease in ICOS+ ILCs was found in lung tissue from IPF patients. IL-5, produced primarily by ILC2s, was significantly reduced after lung injury in ICOS−/− mice, and strikingly, treatment with IL-5 protected both ICOS−/− and wild type mice from mortality. These results imply that low ICOS expression and decreased lung ILC2s in IPF patients may contribute to poor recovery from infections and acute exacerbation, and that IL-5 treatment may be a novel therapeutic strategy to overcome these defects and protect against lung injury.

Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils

“…A growing body of evidence indicates that release of amphiregulin during innate type 2 responses is critical for suppressing inflammation and inducing tissue repair (30). IL-13 and IL-5 have both been demonstrated to protect against acute lung injury, and several recent studies have noted that type 2 cytokines may be protective during sepsis (21,(31)(32)(33)(34)(35). Consistent with these studies, we observed that treatment with IL-5 and IL-13 rescued PLZF -/mice from sepsis, indicating that 1 potential mechanism of IL-33mediated protection is through ILC2 cytokine production.…”

“…Flow cytometry analysis. Lungs were processed as previously described (32). Briefly, perfused lungs were minced and digested with 150 U/ml Collagenase D (Gibco) for 1 hour in DMEM supplemented with 5% FCS.…”

“…For all histology scoring, the scorer was blinded to the mouse treatment, and slides were presented in a random order. The same lung lobe was scored for each mouse (32).…”

T helper 22 cells from Han Chinese patients with atopic dermatitis exhibit high expression of inducible T‐cell costimulator

“…by inducing and regulating Th1, Th2, Th17 and innate lymphoid cell populations. [20][21][22][23][24] Furthermore, recent studies suggest that ICOS-mediated costimulation promotes B-cell differentiation and IgE production. 25 However, little is known about the effects of ICOS/ICOSL in Th22 cell development and AD.…”

“…Over the last two decades, ICOS has been reported to contribute to the pathogenesis of many immune disorders such as cancer, pulmonary sarcoidosis and allergic rhinitis, e.g. by inducing and regulating Th1, Th2, Th17 and innate lymphoid cell populations . Furthermore, recent studies suggest that ICOS‐mediated costimulation promotes B‐cell differentiation and IgE production .…”