Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function
FOXP3<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Tobias Frey (ORCID: https://orcid.org/0000-0002-6274-9864)
- Darina Waltenberger
- Wilfried Ellmeier (ORCID: https://orcid.org/0000-0001-8192-8481)
- Monika Waldherr (ORCID: https://orcid.org/0000-0003-1284-0616)
- Lena Müller (ORCID: https://orcid.org/0000-0002-6351-1786)
- Marlis Alteneder
- Benedikt Agerer (ORCID: https://orcid.org/0000-0002-0044-8396)
- Michael Schuster (ORCID: https://orcid.org/0000-0003-2975-8969)
- Thomas Krausgruber (ORCID: https://orcid.org/0000-0002-1374-0329)
- Teresa Preglej (ORCID: https://orcid.org/0000-0002-7042-199X)
- Ramona Rîca (ORCID: https://orcid.org/0000-0001-5501-8513)
- Sylvia Knapp (ORCID: https://orcid.org/0000-0001-9016-5244)
- Patricia Hamminger
- Christoph Bock (ORCID: https://orcid.org/0000-0001-6091-3088)
- Nicole Boucheron (ORCID: https://orcid.org/0000-0002-4979-8311)
- Andreas Bergthaler (ORCID: https://orcid.org/0000-0003-0597-1976)
- Klaus G. Schmetterer (ORCID: https://orcid.org/0000-0001-9328-4871)
- Daniela Hainberger (ORCID: https://orcid.org/0000-0003-2114-3038)
- Michael A Trauner (ORCID: https://orcid.org/0000-0002-1275-6425)
- Valentina Stolz
- Anastasiya Hladik
- Clarissa Campbell
- Rafael de Freitas e Silva
- Ci Zhu
Institutions
- Austrian Academy of Sciences (AT)
- Austrian Research Institute for Artificial Intelligence (AT)
- Institute of Art (PL)
- CeMM Research Center for Molecular Medicine (AT)
- Institute of Immunology (HR)
- Medical University of Vienna (AT)
Publication Details
- Journal
- eLife
- Published
- 2024-09-26
- DOI
- https://doi.org/10.7554/elife.78738
- Citations
- 2
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.48
Funders
- L'Oreal USA
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Universität Wien
- Medizinische Universität Wien