Short-Chain Fatty Acids Augment Differentiation and Function of Human Induced Regulatory T Cells

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Mingjing Hu - , University of Sydney, Nepean Hospital (Author)
  • Bilal Alashkar Alhamwe - , University of Marburg, International University for Science and Technology (IUST) (Author)
  • Brigitte Santner-Nanan - , University of Sydney (Author)
  • Sarah Miethe - , University of Marburg (Author)
  • Hani Harb - , Institute of Medical Microbiology and Virology, Int Inflammat VIVO Network, University of Marburg, Heidelberg University , TUD Dresden University of Technology, Dalhousie University (Author)
  • Harald Renz - , University of Marburg (Author)
  • Daniel P. Potaczek - , University of Marburg (Author)
  • Ralph K. Nanan - , University of Sydney (Author)

Abstract

Regulatory T cells (Tregs) control immune system activity and inhibit inflammation. While, in mice, short-chain fatty acids (SCFAs) are known to be essential regulators of naturally occurring and in vitro induced Tregs (iTregs), data on their contribution to the development of human iTregs are sparse, with no reports of the successful SCFAs-augmented in vitro generation of fully functional human iTregs. Likewise, markers undoubtedly defining human iTregs are missing. Here, we aimed to generate fully functional human iTregs in vitro using protocols involving SCFAs and to characterize the underlying mechanism. Our target was to identify the potential phenotypic markers best characterizing human iTregs. Naive non-Treg CD4(+) cells were isolated from the peripheral blood of 13 healthy adults and cord blood of 12 healthy term newborns. Cells were subjected to differentiation toward iTregs using a transforming growth factor beta (TGF-beta)-based protocol, with or without SCFAs (acetate, butyrate, or propionate). Thereafter, they were subjected to flow cytometric phenotyping or a suppression assay. During differentiation, cells were collected for chromatin-immunoprecipitation (ChIP)-based analysis of histone acetylation. The enrichment of the TGF-beta-based protocol with butyrate or propionate potentiated the in vitro differentiation of human naive CD4(+) non-Tregs towards iTregs and augmented the suppressive capacity of the latter. These seemed to be at least partly underlain by the effects of SCFAs on the histone acetylation levels in differentiating cells. GITR, ICOS, CD39, PD-1, and PD-L1 were proven to be potential markers of human iTregs. Our results might boost the further development of Treg-based therapies against autoimmune, allergic and other chronic inflammatory disorders.

Details

Original languageEnglish
Article number5740
Number of pages17
JournalInternational journal of molecular sciences
Volume23
Issue number10
Publication statusPublished - May 2022
Peer-reviewedYes

External IDs

PubMedCentral PMC9143307
Scopus 85130399404
WOS 000803436100001
PubMed 35628549
ORCID /0000-0001-8218-2538/work/173988774

Keywords

Sustainable Development Goals

Keywords

  • Butyrates/metabolism, Cell Differentiation, Fatty Acids, Volatile/metabolism, Histones/metabolism, Humans, Infant, Newborn, Propionates/metabolism, T-Lymphocytes, Regulatory/drug effects, Transforming Growth Factor beta/metabolism