%0 Journal Article
%T Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma.
%A Bick F
%A Brenis Gómez CM
%A Lammens I
%A Van Moorleghem J
%A De Wolf C
%A Dupont S
%A Dumoutier L
%A Smith NP
%A Villani AC
%A Browaeys R
%A Alladina J
%A Haring AM
%A Medoff BD
%A Cho JL
%A Bigirimana R
%A Vieira J
%A Hammad H
%A Blanchetot C
%A Schuijs MJ
%A Lambrecht BN
%J J Allergy Clin Immunol
%V 0
%N 0
%D 2024 Aug 13
%M 39147327
%F 14.29
%R 10.1016/j.jaci.2024.07.024
%X <B>BACKGROUND: </B>Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes.<BR><B>OBJECTIVE: </B>IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown.<BR><B>METHODS: </B>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 allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups.<BR><B>RESULTS: </B>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, that controlled TH2 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, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) 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.<BR><B>CONCLUSIONS: </B>IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.