Intrinsic IRG1-itaconate axis in CD4+ T cells inhibits allergic airway inflammation by suppressing the PI3K/Akt/mTOR pathway

The regulatory role of IRG1-itaconate in innate cells has been well established, however, its function in T cells remains elusive. Allergic asthma is a type 2 inflammatory disease and Th2 cells are the canonical producers of type 2 cytokines. Here, we show that IRG1 expression was upregulated in CD4 + T cells in HDM-induced allergic asthma model, accompanied by increased itaconate levels in BALF. Irg1 −/− or conditional knockout Irg1 in T cells exacerbated allergic airway inflammation with more pronounced CD4 + T cells activation and Th2 differentiation. In vitro study showed the deficiency of IRG1 in CD4 + T cells promoted activation and Th2 polarization, associated with enhanced activation of PI3K/Akt/mTOR pathway. These effects were reversed by a PI3K inhibitor or the cell‑permeable itaconate derivative 4‑OI. Using alkylation inhibitor and itaconate‑alkyne probe, we identified PI3K‑p85α as the target protein of itaconate‑mediated alkylation. Mechanistically, 4‑OI directly alkylated PI3K‑p85α at Cys670, and this modification suppressed downstream signaling and T‑cell effector responses. Thus, the intrinsic IRG1-itaconate restrains CD4 + T cells activation and Th2 differentiation by dampening PI3K/Akt/mTOR pathway. Clinically, reduced airway sputum itaconate levels correlate with impaired lung function and enhanced type 2 inflammatory responses in patients with asthma, highlighting IRG1-itaconate axis as a potential therapeutic target for allergic airway inflammation. Our results identify CD4 + T cell-intrinsic itaconate as a regulatory immunometabolite​ shaping adaptive immune response.