Inception of early-life allergen–induced airway hyperresponsiveness is reliant on IL-13 ⁺ CD4 ⁺ T cells

Abstract

Airway hyperresponsiveness (AHR) is a critical feature of wheezing and asthma in children, but the initiating immune mechanisms remain unconfirmed. We demonstrate that both recombinant interleukin-33 (rIL-33) and allergen [house dust mite (HDM) or <i>Alternaria alternata</i>] exposure from day 3 of life resulted in significantly increased pulmonary IL-13⁺CD4⁺ T cells, which were indispensable for the development of AHR. In contrast, adult mice had a predominance of pulmonary Lin^negCD45⁺CD90⁺IL-13⁺ type 2 innate lymphoid cells (ILC2s) after administration of rIL-33. HDM exposure of neonatal IL-33 knockout (KO) mice still resulted in AHR. However, neonatal CD4^creIL-13 KO mice (lacking IL-13⁺CD4⁺ T cells) exposed to allergen from day 3 of life were protected from AHR despite persistent pulmonary eosinophilia, elevated IL-33 levels, and IL-13⁺ ILCs. Moreover, neonatal mice were protected from AHR when inhaled <i>Acinetobacter lwoffii</i> (an environmental bacterial isolate found in cattle farms, which is known to protect from childhood asthma) was administered concurrent with HDM. <i>A. lwoffii</i> blocked the expansion of pulmonary IL-13⁺CD4⁺ T cells, whereas IL-13⁺ ILCs and IL-33 remained elevated. Administration of <i>A. lwoffii</i> mirrored the findings from the CD4^creIL-13 KO mice, providing a translational approach for disease protection in early life. These data demonstrate that IL-13⁺CD4⁺ T cells, rather than IL-13⁺ ILCs or IL-33, are critical for inception of allergic AHR in early life.