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Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation

Dikiy S. et al. (BioRxiv) DOI: 10.1101/2022.05.16.492030

Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation


  • Regulatory T cells

  • Colon inflammation and homeostasis

  • Transgenic murine models

Main Findings

  • The authors of this paper aimed to use novel genetic tools to characterize transcriptional programs of distinct colonic effector Treg cell types

  • Identified a subset of colonic IL-10-producing, terminally differentiated Tregs with functional specialization unaffected by environmental perturbations

  • IL-10-producing T regs deploy other functionally important immunoregulatory mechanisms alongside IL-10 and loss of these cells causes spontaneous inflammation in the colon, rather than loss of IL-10 specifically

  • Transcriptional analysis proposes the idea that Il10stable states disfavour downstream TCR signaling which is present in Il10neg (e.g. Nr4a2 expression)


  • The authors would strengthen their manuscript by identifying the mechanism by which Il10stable Treg function under homeostasis, if TCR-independent and Il10-independent remains unknown.

  • Long-term implications of IL-10 Treg subsets in more chronic inflammatory models remains to be explored.

  • Phenotype and evidence for function of Il10stable Treg population in the colon is largely based on sequencing data, which show only very slight changes reflected by small experimental changes.

  • In addition, it would be of interest if the role of constitutive Il-10 production from the Il10stable Treg population in homeostasis.

  • Impact of the Il10stable Treg population on microbiotal composition remains an avenue to explore especially since Il10stable Treg populations co-express RORgt which are well known for their role in microbiotal tolerance.


For the field, generating these genetic tools may be highly useful for specific groups who study IL-10 immunomodulatory functions, Foxp3 Tregs, or a combination of both

The genetic tools involved are highly specialized however, but does not mean it they cannot be translated to studying other tissues, including the lungs, in tumour models, etc.

For general immunologists, it is interested to note, but perhaps not surprising, that tissue-resident Tregs themselves have functions beyond IL-10 production.

The manuscript highlights the power of these genetic tools used in the study, while the immunological findings may require further expansion.


Reviewed by Vivian Lau as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM).

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