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Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma
Journal article   Open access   Peer reviewed

Interleukin-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, …
Journal of allergy and clinical immunology, Vol.154(5), pp.1129-1145
11/2024
DOI: 10.1016/j.jaci.2024.07.024
PMCID: PMC12255943
PMID: 39147327
url
https://doi.org/10.1016/j.jaci.2024.07.024View
Published (Version of record) Open Access

Abstract

[Display omitted] 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. 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. 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. 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. 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.
 Asthma Monoclonal Antibodies adaptive IL-21 IL-9 innate type 2 immunity

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