Aberrant Th2 Immune Responses Are Associated With a Reduced Frequency of IL-35-Induced Regulatory T Cells After Allergen Exposure in Patients With Allergic Asthma

PURPOSE: Allergen exposure induces aberrant T helper (Th) 2 immune responses in patients with allergic asthma, but not in sensitized asymptomatic and nonallergic subjects. Interleukin (IL)-35-induced regulatory T (iTr35) cells are a new subset of regulatory T cells with immunoregulatory properties. These cells can significantly suppress Th2 responses in seasonal allergic rhinitis. However, it remains unknown whether iTr35 cells are involved in the immunoregulation of allergic asthmatic individuals after specific allergen exposure. METHODS: The iTr35 cell frequency in peripheral blood mononuclear cells (PBMCs) was measured in patients with allergic asthma as well as in asymptomatic and healthy subjects. The difference in naïve CD4(+) T cell conversion to iTr35 cells in vitro during allergen stimulation was also investigated. The effects of iTr35 cells on naïve CD4(+) T cell differentiation into Th2 cells, CD4(+)CD25(−) T (Teff) cell proliferation and Th2 cytokine production in vitro were assessed. RESULTS: Significantly reduced iTr35 cell frequencies and IL-35 expression levels were found in asthmatic patients with Derp1 allergy compared with asymptomatic and healthy subjects. Moreover, the circulating iTr35 cell proportion and IL-35 expression level in asthmatic patients gradually decreased with disease severity. Patients with allergic asthma had reduced transformation of naïve CD4(+) T cells into iTr35 cells and IL-35 production after allergen exposure compared with asymptomatic and healthy subjects. Most importantly, iTr35 cells inhibited allergen-driven differentiation of naïve CD4(+) T cells into Th2 cells, Teff cell proliferation and Th2 cytokine production in an IL-35-dependent manner. CONCLUSIONS: The results of our study suggest that iTr35 cells may play an important role in preventing Th2 responses to allergens by secreting IL-35 and that iTr35 cells may be a potential new immune regulator of allergic asthma.