Abstract
Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.
Highlights
Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood
This study delineates at the single-cell level Treg populations found in the joints of patients with inflammatory spondyloarthritis, identifying both established and unexpected regulatory subsets
Our analysis, surveying over 16,000 Tregs, represents an atlas of the diverse transcriptional phenotypes acquired by Tregs in the blood and synovial fluid (SF) in the course of spondyloarthritis
Summary
Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. Tregs are characterized by expression of the master transcription factor FOXP3 and the interleukin (IL)-2 receptor α-chain CD25, they show considerable functional heterogeneity and utilize diverse suppressive mechanisms including secretion (or sequestration) of soluble mediators, direct cytotoxicity, and contact-dependent receptor inhibition[1] Integrating environmental signals, they can traffic to specific target organs and adopt organ-specific gene signatures and functions[2], while maintaining plasticity within tissues[3]. The phenotype and transcriptional profile of Tregs is yet to be fully delineated, especially at the single-cell level, at many sites of tissue inflammation in humans, including the synovial fluid (SF) in the course of inflammatory arthritis, representing an opportunity for the study of local regulatory mechanisms. The role of effector immunity, and of type 17 immunity in particular, is widely recognized in SpA5, the impact and phenotype of Tregs is largely unknown
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