Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function
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Evaluation Summary:
The study shows that the LXRbeta - NCOR1 axis restricts the terminal differentiation of Treg cells into effector Tregs. It also suggests that, in addition to an impact on effector Treg differentiation, loss of NCOR1 leads to impaired suppression function in Treg cells. The results may contribute to our understanding of Treg cell differentiation and function.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
FOXP3 + regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4 + T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.
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Evaluation Summary:
The study shows that the LXRbeta - NCOR1 axis restricts the terminal differentiation of Treg cells into effector Tregs. It also suggests that, in addition to an impact on effector Treg differentiation, loss of NCOR1 leads to impaired suppression function in Treg cells. The results may contribute to our understanding of Treg cell differentiation and function.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The aim of the research is to show the role of the transcription factor NCOR1-in the differentiation and function of regulatory T cells (Tregs). The study showed that NCOR-1 deficiency increased the fraction of effector Tregs, and enhanced MYC expression in Tregs and that disruption of interaction of LXR with NCOR1 led to an increased MYC expression in in vitro generated Tregs. NCOR1-mediated transcriptional regulation could be potentially important for T cell development and function; however, the results are insufficient for fully supporting their claim that NCOR1 controls Treg differentiation and function, in particular, the study lacks a basic analysis of the role of NCOR1 in Tregs.
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Reviewer #2 (Public Review):
Stolz and colleagues show that murine or human Treg cells deficient in NCOR1 display increased expression of MYC that drives the effector Treg cell differentiation. This effect is restricted mainly to mature Treg cells as it is not associated with thymic changes in Treg development. The impact of NCOR1 in Treg development was also confirmed because NCOR1 repressed the acquisition of an eTreg gene signature by naïve Treg cells. In addition, the authors found that the liver X receptor beta (LXRbeta, a cholesterol sensor involved in the cholesterol biosynthesis) could interact with NCOR1. Agonists of LXRbeta disrupted LXRbeta-NCOR1 interactions, leading to MYC upregulation that phenocopied the outcome of NCOR1-deficiency. Finally, the authors showed that NCOR1-deficiency in Treg cells, although supporting the …
Reviewer #2 (Public Review):
Stolz and colleagues show that murine or human Treg cells deficient in NCOR1 display increased expression of MYC that drives the effector Treg cell differentiation. This effect is restricted mainly to mature Treg cells as it is not associated with thymic changes in Treg development. The impact of NCOR1 in Treg development was also confirmed because NCOR1 repressed the acquisition of an eTreg gene signature by naïve Treg cells. In addition, the authors found that the liver X receptor beta (LXRbeta, a cholesterol sensor involved in the cholesterol biosynthesis) could interact with NCOR1. Agonists of LXRbeta disrupted LXRbeta-NCOR1 interactions, leading to MYC upregulation that phenocopied the outcome of NCOR1-deficiency. Finally, the authors showed that NCOR1-deficiency in Treg cells, although supporting the differentiation of eTreg cells, failed to prevent colitis upon adoptive cell transfer into lymphopenic mice transferred with CD4+ T cells. This observation was interpreted as evidence that NCOR1, besides having an impact on eTreg cell differentiation, can also be essential to maintaining the suppressive function of Treg cells.
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