T-Cell IRG1-Itaconate Axis Inhibits Allergic Airway Inflammation

An intrinsic IRG1-itaconate axis in CD4+ T cells suppresses allergic airway inflammation by dampening the PI3K/Akt/mTOR signaling pathway, according to a study published in Cellular and Molecular Life Sciences. While the regulatory role of IRG1-itaconate in innate immune cells was previously established, its functional role in T cells had remained elusive. In an experimental house dust mite-induced allergic asthma model, researchers observed that IRG1 expression was upregulated in CD4+ T cells alongside increased levels of the metabolite itaconate in bronchoalveolar lavage fluid.

To determine the physiological role of this pathway in vivo, the investigators evaluated mice with global Irg1 deficiency as well as mice with a conditional knockout of Irg1 restricted to T cells. In both models, the absence of IRG1 significantly exacerbated allergic airway inflammation. This worsening of disease was characterized by more pronounced CD4+ T cell activation and enhanced differentiation of Th2 cells, which serve as canonical producers of type 2 cytokines in allergic asthma.

In vitro experiments corroborated these findings, demonstrating that IRG1 deficiency directly promoted the activation and Th2 polarization of CD4+ T cells. The enhanced activation and polarization were linked to heightened activity of the PI3K/Akt/mTOR signaling pathway. When researchers treated the deficient cells with a PI3K inhibitor or with 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, the excessive cellular activation and differentiation phenotypes were successfully reversed.

To elucidate the molecular mechanism underlying this inhibition, the team utilized an alkylation inhibitor alongside an itaconate-alkyne probe, identifying PI3K-p85α as the direct target protein of itaconate-mediated alkylation. Further analysis revealed that 4-OI directly alkylates PI3K-p85α at the Cys670 residue. This specific post-translational modification suppressed downstream kinase signaling cascades and restrained T-cell effector responses, confirming that cell-intrinsic itaconate acts directly on this pathway.

The investigators also assessed the clinical relevance of these findings in human patients with asthma, discovering that reduced itaconate levels in airway sputum correlate with impaired lung function and heightened type 2 inflammatory responses. The authors concluded that CD4+ T cell-intrinsic itaconate functions as a regulatory immunometabolite that shapes adaptive immune responses, highlighting the IRG1-itaconate axis as a promising therapeutic target for allergic airway inflammation.

Subject of Research: CD4+ T cell immunometabolism and allergic airway inflammation

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

Article References: Wang, Q., Gao, L., Wu, M., Liu, H., Lin, Y., Zhou, J., Huang, J., Jiang, H., Qu, S., Huang, Y., & Han, J. (2026). Intrinsic IRG1-itaconate axis in CD4+ T cells inhibits allergic airway inflammation by suppressing the PI3K/Akt/mTOR pathway. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06495-5

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06495-5

Keywords: IRG1, itaconate, CD4+ T cells, allergic asthma, airway inflammation, PI3K/Akt/mTOR pathway, Th2 differentiation, immunometabolism, Intrinsic, IRG1-itaconate, axis, cells