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

Abstract

T cell heterogeneity is highly relevant to allergic disorders. We resolved the heterogeneity of human tissue CD3+ T cells during allergic inflammation, focusing on a tissue-specific allergic disease, eosinophilic esophagitis (EoE). We investigated 1088 single T cells 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-like (GATA3+) 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 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.

• Authors: Ting Wen, Bruce J Aronow, Yrina Rochman, Mark Rochman, Kiran Kc, Phil J Dexheimer, Philip Putnam, Vincent Mukkada, Heather Foote, Kira Rehn, Sam Darko, Daniel Douek, Marc E Rothenberg
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 5 Pg. 2014-2028 (04 08 2019) ISSN: 1558-8238 [Electronic] United States
• PMID: 30958799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• GATA3 Transcription Factor
• GATA3 protein, human
• IL5 protein, human
• Interleukin-13
• Interleukin-5
• Ligands

Topics

• Adolescent
• Animals
• Biopsy
• CD3 Complex (analysis)
• Cell Separation
• Child
• Child, Preschool
• Computational Biology
• Endoscopy
• Eosinophilic Esophagitis (genetics, immunology)
• Female
• Flow Cytometry
• GATA3 Transcription Factor (immunology)
• Humans
• Inflammation
• Interleukin-13 (immunology)
• Interleukin-5 (immunology)
• Ligands
• Lung (metabolism)
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred BALB C
• Phenotype
• Sequence Analysis, RNA (methods)
• Single-Cell Analysis (methods)
• T-Lymphocytes (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Th2 Cells (immunology)