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- Title
TSLP shapes the pathogenic responses of memory CD4<sup>+</sup> T cells in eosinophilic esophagitis.
- Authors
Rochman, Yrina; Kotliar, Michael; Ben-Baruch Morgenstern, Netali; Barski, Artem; Wen, Ting; Rothenberg, Marc E.
- Abstract
The cytokine thymic stromal lymphopoietin (TSLP) mediates type 2 immune responses, and treatments that interfere with TSLP activity are in clinical use for asthma. Here, we investigated whether TSLP contributes to allergic inflammation by directly stimulating human CD4+ T cells and whether this process is operational in eosinophilic esophagitis (EoE), a disease linked to variants in TSLP. We showed that about 10% of esophageal-derived memory CD4+ T cells from individuals with EoE and less than 3% of cells from control individuals expressed the receptor for TSLP and directly responded to TSLP, as determined by measuring the phosphorylation of STAT5, a transcription factor activated downstream of TSLP stimulation. Accordingly, increased numbers of TSLP-responsive memory CD4+ T cells were present in the circulation of individuals with EoE. TSLP increased the proliferation of CD4+ T cells, enhanced type 2 cytokine production, induced the increased abundance of its own receptor, and modified the expression of 212 genes. The epigenetic response to TSLP was associated with an enrichment in BATF and IRF4 chromatin-binding sites, and these transcription factors were induced by TSLP, providing a feed-forward loop. The numbers of circulating and esophageal CD4+ T cells responsive to TSLP correlated with the numbers of esophageal eosinophils, supporting a potential functional role for TSLP in driving the pathogenesis of EoE and providing the basis for a blood-based diagnostic test based on the extent of TSLP-induced STAT5 phosphorylation in circulating CD4+ T cells. These findings highlight the potential therapeutic value of TSLP inhibitors for the treatment of EoE. Editor's summary: The epithelial-derived cytokine TSLP is increased in abundance in the tissues of patients with allergic disorders, including eosinophilic esophagitis (EoE). TSLP induces the differentiation and maintenance of murine T helper 2 (TH2) cells, which secrete type 2 cytokines to maintain allergic responses. Rochman et al. found a subset of TSLP-responsive memory CD4+ T cells that were increased in number in the blood and esophageal tissue of patients with EoE. These pathogenic TH2-like cells produced type 2 cytokines and exhibited feed-forward signaling to increase TSLP receptor abundance. These findings suggest that anti-TSLP therapy should be further explored for the treatment of EoE. —John F. Foley
- Subjects
IMMUNOLOGIC memory; EOSINOPHILIC esophagitis; THYMIC stromal lymphopoietin; T cells; IMMUNE response; ADRENERGIC beta agonists
- Publication
Science Signaling, 2023, Vol 16, Issue 802, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adg6360