Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma.
(2024) The Journal of allergy and clinical immunology — Vol. aug 13, n° 24, p. S0091-6749 (2024)
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- Abstract
- Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by T2 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 T2 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 T2 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 T2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
- Affiliations
VIB Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research,
Citations
Bick, F., Brenis Gómez, C. M., Lammens, I., Van Moorleghem, J., De Wolf, C., Dupont, S., Dumoutier, L., Smith, N. P., Villani, A.-C., Browaeys, R., Alladina, J., Haring, A. M., Medoff, B. D., Cho, J. L., Bigirimana, R., Vieira, J., Hammad, H., Blanchetot, C., Schuijs, M. J., & Lambrecht, B. N. (2024). Interleukin-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma. The Journal of allergy and clinical immunology, aug 13(24), S0091-6749. https://doi.org/10.1016/j.jaci.2024.07.024 (Original work published 2024)