Single-cell RNA sequencing of inflammatory tissue T cells in eosinophilic esophagitis

T cell heterogeneity is highly relevant to allergic disorders. We resolve the heterogeneity of human tissue CD3+ T cells during allergic inflammation, focusing on a tissue-specific allergic disease, eosinophilic esophagitis (EoE). We investigated 1,088 single T cell derived from patients with a spectrum of disease activity. Eight disparate tissue T cell subtypes (designated T1-T8) were identified, with T7 and T8 enriched in the diseased tissue. The phenotypes of T7 and T8 resemble putative TREG (FOXP3+) and effector Th2 (GATA3+)-like cells, respectively. Prodigious levels of IL-5 and IL-13 were confined to HPGDS+ CRTH2+ IL-17RB+ FFAR3+CD4+ T8 effector Th2 cells. EoE severity closely paralleled a lipid/fatty acid–induced activation node highlighted by the expression of the short-chain fatty acid receptor FFAR3. Ligands for FFAR3 induced Th2 cytokine production from human and murine T cells including in an in vivo allergy model. Therefore, we have elucidated the defining characteristics of tissue-residing CD3+ T cells in EoE, a specific enrichment of CD4+ TREG and effector Th2 cells, confinement of type 2 cytokine production to the CD4+ effector population, a highly likely role for FFAR3 in amplifying local Th2 responses in EoE, and a resource to further dissect tissue lymphocytes and allergic responses. Single-cell transcriptome profililng of esophagus biopsies from patients with active eosinophilic esophagitis (EoE, n=11), in remission (n=6), and without disease (n=5)