Airway but Not Blood Type 2 Innate Lymphoid Cells (ILC2s) from Asthmatic Patients Are Steroid-Resistant, Which Is Induced By IL7R-Alpha Ligands

Rationale: The ILC2 is a new type 2 immune cell.  We previously reported that the ILC2 frequency was increased in the airways in asthma.  Its response to steroids is unknown. 

Methods: ILC2s were isolated from bronchoalveolar lavage and blood from asthmatic patients and disease controls and analyzed by flow cytometry and ELISA as described previously (Christianson et al, JACI 136:59; 2015).   

Results: Culture of human blood ILC2s (lin-CRTH2+IL7Rα+) from asthmatic patients with dexamethasone (dex) (10^-7M)) inhibited IL5+ ILC2s by 77±12% (N=16).   In contrast, culture of BAL cells with dex inhibited IL5+ILC2s by only 21±14% (N=10) suggesting a relative steroid resistance.  Two IL7Rα ligands--IL7 and TSLP induced steroid resistance in IL5+ILC2s in vitro.  In contrast, IL2-, IL25- and IL33-treated ILC2s remained steroid sensitive.   Dex increased IL7Rα expression by 171±16% in ILC2s and reduced the threshold for IL7- and TSLP-induced STAT5 activation by half.  IL7 and TSLP increased the expression of PLZF (ZBTB16), a transcriptional repressor/activator.  Both STAT5 and PLZF are known to interact with the glucocorticoid receptor and block its nuclear function.  We observed sustained STAT5 phosphorylation in IL7/TSLP but not IL2/IL33-stimulated ILC2s.  Inhibition of STAT5 by Tofacitinib reversed steroid resistances of ILC2s. TSLP was elevated in BAL from select asthmatic patients, which negatively correlated (r=-0.62) with dex-inhibition of BAL IL5+ILC2.   

Conclusions: Airway but not blood ILC2s from asthmatic patients are relatively steroid-resistant, which is induced by IL7 and TSLP, and is mediated by sustained STAT5 signaling and heightened PLZF expression.  STAT5 inhibitors and anti-IL7/TSLP modalities are likely to benefit steroid-resistant asthma.