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…
Inflammation in barrier tissues can result in heightened responses during subsequent encounters with the same stimulus. Researchers have long assumed that such recall responses tend to reinforce the original type of inflammation, whether that be Type 1, Type 2, or Type 17. To investigate how memory responses interact with inflammation types beyond the initial one, scientists used well-studied murine models of T2 atopic dermatitis and T17 psoriasis-like inflammation.
They compared how these models stored and recalled inflammation using single-cell RNA sequencing over time.
During T17 inflammation, a network of IL-17-producing gamma delta T cells, IL-17-responsive keratinocytes, and myeloid cells that formed in the initial challenge reappeared during recall with higher numbers and faster rates. However, T2 inflammation produced a strikingly amplified and persistent recall response with signs of Type 1 immunity.
This included elevated interferon signaling and recruitment of cytotoxic lymphocytes, which were not normally seen in T2 responses. The shift towards a T1-like response was triggered by tissue-resident memory CD8+ T cells that grew larger with each challenge. These cells released IFN-gamma, TNF-, and IL-13, which resembled the characteristics of treatment-resistant CD8+ T cells seen in atopic dermatitis.
The changes in the T2 memory were influenced by the release of cytokines such as IFN-gamma, TNF-, and IL-13 from CD8+ Trm cells. Additionally, the T2 environment rich in IL-4 worked together with the T1-promoting cytokines produced by Trm cells to amplify the allergic recall process. This amplification was facilitated through IL-15 and CCL19, which came from fibroblasts.
By manipulating fibroblast responsiveness to IFN, researchers were able to uncover how this CD8+ T cell-fibroblast circuit supports cytotoxic responses in allergic immunity. The study also found that this mechanism was the same in human atopic dermatitis, demonstrating the relevance of this fibroblast-CD8+ T cell circuit in driving a Type 1 immune axis that supports allergic inflammatory memory.
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