IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2-type 3 inflammation via TCR-independent, innate-like reactivation of memory T cells - identifying a novel pathogenic axis in CRSwNP. 2. CD8 + T cells emerge as significant and previously underappreciated sources of type 2 cytokines (IL-5/IL-13) within this mixed inflammatory milieu. 3. Therapeutic targeting of the IL-2-JAK-STAT pathway shows clinical potential, with JAK inhibitors effectively suppressing mixed inflammatory responses in CRSwNP. IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2-type 3 inflammation via TCR-independent, innate-like reactivation of memory T cells - identifying a novel pathogenic axis in CRSwNP. CD8 + T cells emerge as significant and previously underappreciated sources of type 2 cytokines (IL-5/IL-13) within this mixed inflammatory milieu. Therapeutic targeting of the IL-2-JAK-STAT pathway shows clinical potential, with JAK inhibitors effectively suppressing mixed inflammatory responses in CRSwNP. Chronic rhinosinusitis with nasal polyps (CRSwNP) involves mixed type 2-type 3 inflammation, associated with disease severity and treatment resistance, yet mechanisms remain unclear. To investigate the role of IL-2 and its interaction with type 3 inducers (TNF-α, IL-1β, and IL-23) in driving mixed type 2-type 3 inflammation. IL-2 and receptor expression in nasal polyps (NPs) was analyzed using tissue homogenates and public RNA-seq data. Dispersed NP cells (DNPCs) were treated with IL-2/type 3 inducers, with cytokine production, proliferation, and gene expression analyzed via immunoassays, flow cytometry, and RNA-seq. IL-2 receptor/JAK blockade studies were conducted. Furthermore, CD4 + and CD8 + T cells were magnetically isolated from NPs to evaluate their response to cytokine stimulation. IL-2 levels were increased in CRSwNP, particularly in type 3-dominant and mixed type 2-type 3 subgroups, and correlated with type 3 cytokines. RNA-seq supported upregulated IL-2 receptors and their co-expression with type 3 genes. IL-2 synergized with type 3 inducers to enhance both type 2 and type 3 cytokine production in DNPCs. Direct functional evidence from isolated CD4 + and CD8 + T cells confirmed this synergy, with CD8 + T cells emerging as a novel source of IL-13. Flow cytometry further supported these findings, showing synergistic cytokine production across diverse cell populations, including T cell subsets and NK cells. Memory T cells mediated TCR-independent cytokine production. Transcriptomic analysis identified activated type 3, type 2, and JAK-STAT signaling pathways. IL-2 receptor blockade, particularly JAK inhibition, attenuated IL-2/type 3 inducer-mediated synergistic inflammation. We identify a novel mechanism whereby IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2-type 3 inflammation via innate-like T cell activation, and validate targeted JAK inhibition as a potential therapy.
Wang et al. (Sun,) studied this question.