IL-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma
Fabian Bick, Claudia M Brenis Gómez, Inés Lammens, Justine Van Moorleghem, Caroline De Wolf, Sam Dupont, Laure Dumoutier, Neal P. Smith, Alexandra–Chloé Villani, Robin Browaeys, Jehan Alladina, Alexis M. Haring, Benjamin D. Medoff, Josalyn L. Cho, René Bigirimana, Joao Vieira, Hamida Hammad, Christophe Blanchetot, Martijn J. Schuijs, Bart N. Lambrecht
Abstract
Background Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5, and IL-13 cytokines produced by T H 2 lymphocytes or type 2 innate lymphoid cells (ILC2s). IL-2 family cytokines play a key role in the differentiation, homeostasis, and effector function of innate and adaptive lymphocytes. Objective IL-9 and IL-21 boost activation and proliferation of T H 2 and ILC2s, but the relative importance and potential synergism between these γ common chain cytokines are currently unknown. Methods Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human subjects with allergic asthma compared with nonasthmatic controls. Here, we also measured IL-21 in both groups. Results IL-9 played a central role in controlling innate IL-33–induced lung inflammation by promoting proliferation and activation of ILC2s in an IL-21–independent manner. Conversely, chronic house dust mite–induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, which controlled T H 2 activation, eosinophilia, total serum IgE, and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, as combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage samples we measured elevated IL-21 protein within the allergic asthmatic group compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets. Conclusions IL-9 and IL-21 play important and nonredundant roles in allergic asthma by boosting ILC2s and T H 2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.