CCR8⁺ST2⁺ tissue-resident regulatory T cells constrain type 2 immunity to environmental allergens in the lungs.

Abstract

Allergic asthma is characterized by dysregulated type 2 immunity to environmental antigens. However, our knowledge is limited regarding how type 2 immune responses are regulated during chronic airway inflammation. CD4⁺Foxp3⁺ T regulatory (Treg) cells specialize in the maintenance of immune homeostasis. This study aimed to identify the population of Treg cells that play a key role in regulating allergen-induced type 2 immune responses. Naive mice were intranasally exposed to fungus Alternaria alternata extract or house dust mite for up to 6 weeks. We characterized the phenotypes, tissue localization, and temporal dynamics of Treg cell subpopulations. In vivo functions were assessed using mice deficient in Treg cells or Ccr8, as well as wild-type mice treated with anti-IL-10R blocking antibody. Depletion of Treg cells or blockade of the IL-10 pathway exacerbated type 2 airway inflammation in mice exposed to Alternaria. Multiple Treg cell subsets were identified in the lungs after Alternaria exposure. Among them, CCR8⁺ST2⁺ Treg cells exhibited T_H2-like gene expression profiles, highly upregulated molecules associated with immunoregulatory functions, and effectively suppressed CD4⁺ T-cell proliferation. Upon repeated airborne allergen exposure in vivo, CCR8⁺ST2⁺ Treg cells accumulated within lung tissue and displayed long-term persistence. Genetic deletion of Ccr8 rendered mice susceptible to low-dose allergens, which was tolerated by wild-type mice, resulting in lung pathology similar to human asthma. Tissue-resident CCR8⁺ST2⁺ Treg cells in the lungs play a key role in constraining type 2 immunity and preventing allergen-induced immunopathology in response to environmental allergen exposure.