LAUSR

Severe asthma remains a clinical burden despite the emergence of antibody therapies. Complex disease drivers, which shift between T2, T1 and T17 driven inflammation, termed mixed T cell asthma, likely contribute to ineffective disease control in this population. Here we dissect the mechanisms underlying severe asthma to reveal a potential role (s) for both PI3Kgamma and delta (PI3Kγ and δ) isoform activity in asthmatics with a mixed T cell endotype. A PI3Kγδ gene signature was generated from next generation sequencing of IL-8/GM-CSF-stimulated monocytes where PI3Kγδ signalling was inhibited. This mRNA signature was used to interrogate the Ubiopred database. We observed a strong association between PI3Kγδ pathway activity, severity and mixed eosinophil and neutrophil sputum granulocyte content. To further support a role of PI3Kγδ in a mixed T cell asthma phenotype we demonstrated the following. 1) PI3Kδ-dependent allergen stimulation of mixed T cell activity in grass pollen atopic blood. 2) PI3Kδ-mediated inhibition of IL-5, IFNγ and IL-17 production from asthma patient blood T cells. 3) PI3Kγ mediated signalling was required for activation of asthmatic eosinophil and neutrophil populations. 4) Activity of an inhaled PI3Kγδ dual inhibitor in a rodent in vivo model of steroid resistant allergy/infection on mixed T cell mediator release, granulocyte influx and airways hyperresponsiveness. These data identify a population of mixed T cell asthma patients with increased PI3Kγδ activity and suggest a therapeutic potential of an inhaled PI3K dual inhibitor.