D1.435 - A TSLP Tuft Cell-Treg Cell Circuit promotes Food Allergy

The intestinal epithelium plays an active role in establishing tolerance to dietary antigens by shaping local innate and regulatory immune networks. In food allergy (FA), however, epithelial signaling becomes reprogrammed toward promoting sensitization. Tuft cells emerge as a critical epithelial subset, and tuft‑cell‑derived thymic stromal lymphopoietin (TSLP) has been identified as a potential initiator of this maladaptive shift.

Using murine models of FA, we employed tuft‑cell‑specific deletion of Tslp to investigate the functional role of tuft‑cell‑derived TSLP in allergic sensitization and anaphylaxis. We assessed TSLP receptor (TSLPR) expression in regulatory T cells (Treg cells) from FA‑prone F709 mice, wild‑type mice undergoing epicutaneous sensitization, and human FA patients. Transcriptomic analyses were performed to compare TSLPR⁺ and TSLPR⁻ Treg subsets. Additionally, Treg‑specific deletion of Crlf2 (encoding TSLPR) was used to evaluate the contribution of Treg‑intrinsic TSLPR signaling to FA pathogenesis.

Tuft‑cell‑specific deletion of Tslp markedly reduced allergic sensitization and anaphylaxis, establishing tuft‑cell‑derived TSLP as a key driver of FA. Treg cells upregulated TSLPR in FA‑prone mice and during epicutaneous sensitization, and TSLPR⁺ Treg cells displayed a distinct transcriptional signature. Loss of tuft‑cell‑derived TSLP reduced TSLPR expression on Treg cells, prompting further investigation of TSLPR regulation. Treg‑specific deletion of Crlf2 ameliorated FA and increased the frequency of RORγt⁺ tolerogenic Treg cells. In human FA patients, circulating Treg cells showed elevated TSLPR expression, which declined in individuals undergoing oral immunotherapy combined with omalizumab.

These findings reveal a previously unrecognized epithelial–immune circuit in which tuft‑cell‑derived TSLP shapes Treg‑cell function to promote food allergy. This TSLP–TSLPR axis represents a critical epithelial signal influencing immune responses to dietary antigens and may provide new therapeutic targets for FA.