Journal Article

Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function

Agerer, Benedikt, Bergthaler, Andreas, Bock, Christoph, Boucheron, Nicole, Hamminger, Patricia, Hainberger, Daniela, Krausgruber, Thomas, Campbell, Clarissa, Zhu, Ci, Trauner, Michael, Frey, Tobias, Knapp, Sylvia, Preglej, Teresa, Ellmeier, Wilfried, Rica, Ramona, de Freitas e Silva, Rafael, Hladik, Anastasiya, Schuster, Michael, Waltenberger, Darina, Alteneder, Marlis, Stolz, Valentina, Müller, Lena, Waldherr, Monika, Schmetterer, Klaus

2024

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / autoimmunity / CD4 antigen / Cell Differentiation / Cell growth / Cholesterol / Clonal deletion / Colitis / Colitis - genetics / Colitis - immunology / Effector cells / Epigenetic inheritance / Epigenetics / Foxp3 protein / Gene deletion / Gene expression / Genetic research / Genetic transcription / Hepatocytes / Homeostasis / Humans / Immunology and Inflammation / Immunoregulation / Liver X receptors / Liver X Receptors - genetics / Liver X Receptors - metabolism / Lymphatic system / Lymphocytes / Lymphocytes T / Mice / Mice, Inbred C57BL / Mice, Knockout / Nuclear Receptor Co-Repressor 1 - genetics / Nuclear Receptor Co-Repressor 1 - metabolism / regulatory T cells / T cells / T lymphocyte subsets / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / T-Lymphocytes, Regulatory - immunology / Transcription factors