A fibroblast-CD8+ T cell circuit drives a Type 1 shift in allergic inflammatory memory

Inflammatory memory in barrier tissues often manifests as exaggerated recall responses to previously encountered stimuli. While recall is generally thought to reinforce the Type of inflammation (e.g., Type 1 (T1), Type 2 (T2), or Type 17 (T17)) induced in the primary encounter, whether and how memory responses engage programs beyond the initiating Type is unclear. Here, we adapted well-characterized murine models of T2 atopic dermatitis (AD)-like and T17 psoriasis-like inflammation into repeated challenge paradigms to compare how inflammatory memory is stored and recalled through longitudinal single-cell RNA-sequencing. In T17 inflammation, a network of IL-17-producing γδT cells, IL-17-responsive keratinocytes and myeloid cells established in primary challenge re-emerged in recall with increased abundance and accelerated kinetics. By contrast, allergic T2 memory drove a particularly exacerbated and durable recall response in which hallmark features of T1 immunity, including interferon (IFN) signaling and cytotoxic lymphocyte recruitment, were unexpectedly layered onto amplified T2 responses. This T2-to-T1 shift was initiated by CD8+ tissue-resident memory T (Trm) cells that expanded with repeated challenge, produced IFNγ, TNF-α and IL-13, and closely resembled treatment-refractory Trm cells in AD. Tissue rewiring was supported by Trm-derived T1 cytokines and the IL-4-rich T2 milieu whose synergy on fibroblasts amplified allergic recall via IL-15 and CCL19. By tuning fibroblast IFN responsiveness in vivo, we mechanistically dissect how this fibroblast-CD8+ T cell circuit supports cytotoxic CD8+ T cell responses. In human AD, both arms of allergic recall amplification by this two-cell circuit featuring T1 and T2 effector responses were conserved. Our findings reveal how a stromal-immune circuit drives a clinically relevant T1 immune axis to support allergic inflammatory memory.