Rbpj expression in regulatory T cells is critical for restraining TH2 responses

Michael Delacher; Christian Schmidl; Yonatan Herzig; Minka Breloer; Wiebke Hartmann; Fabian Brunk; Danny Kägebein; Ulrike Träger; Ann-Cathrin Hofer; Sebastian Bittner; Dieter Weichenhan; Charles D Imbusch; Agnes Hotz-Wagenblatt; Thomas Hielscher; Achim Breiling; Giuseppina Federico; Hermann-Josef Gröne; Roland M Schmid; Michael Rehli; Jakub Abramson; Markus Feuerer

doi:10.1038/s41467-019-09276-w

Rbpj expression in regulatory T cells is critical for restraining T_H2 responses

Nat Commun. 2019 Apr 8;10(1):1621. doi: 10.1038/s41467-019-09276-w.

Authors

Michael Delacher^{1

2

3}, Christian Schmidl², Yonatan Herzig⁴, Minka Breloer⁵, Wiebke Hartmann⁵, Fabian Brunk⁶, Danny Kägebein³, Ulrike Träger³, Ann-Cathrin Hofer³, Sebastian Bittner^{1

2}, Dieter Weichenhan⁷, Charles D Imbusch⁸, Agnes Hotz-Wagenblatt⁹, Thomas Hielscher¹⁰, Achim Breiling¹¹, Giuseppina Federico¹², Hermann-Josef Gröne¹², Roland M Schmid¹³, Michael Rehli^{2

14}, Jakub Abramson⁴, Markus Feuerer^{15

16

17}

Affiliations

¹ Chair for Immunology, University Regensburg and University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
² Regensburg Center for Interventional Immunology (RCI), University Regensburg and University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
³ Immune Tolerance Group, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁴ Department of Immunology, Weizmann Institute of Science, 234 Herzl Street, 76100, Rehovot, Israel.
⁵ Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Straße 74, 20359, Hamburg, Germany.
⁶ Division of Developmental Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁷ Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁸ Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
⁹ Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
¹⁰ Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
¹¹ Division of Epigenetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
¹² Division of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
¹³ Department of Internal Medicine, Technical University of Munich, Ismaninger Straße 22, 81675, Munich, Germany.
¹⁴ Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
¹⁵ Chair for Immunology, University Regensburg and University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. [email protected].
¹⁶ Regensburg Center for Interventional Immunology (RCI), University Regensburg and University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. [email protected].
¹⁷ Immune Tolerance Group, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. [email protected].

Abstract

The transcriptional regulator Rbpj is involved in T-helper (T_H) subset polarization, but its function in T_reg cells remains unclear. Here we show that T_reg-specific Rbpj deletion leads to splenomegaly and lymphadenopathy despite increased numbers of T_reg cells with a polyclonal TCR repertoire. A specific defect of Rbpj-deficient T_reg cells in controlling T_H2 polarization and B cell responses is observed, leading to the spontaneous formation of germinal centers and a T_H2-associated immunoglobulin class switch. The observed phenotype is environment-dependent and can be induced by infection with parasitic nematodes. Rbpj-deficient T_reg cells adopt open chromatin landscapes and gene expression profiles reminiscent of tissue-derived T_H2-polarized T_reg cells, with a prevailing signature of the transcription factor Gata-3. Taken together, our study suggests that T_reg cells require Rbpj to specifically restrain T_H2 responses, including their own excessive T_H2-like differentiation potential.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / immunology
Disease Models, Animal
Female
GATA3 Transcription Factor / metabolism
Gene Expression Profiling
Gene Expression Regulation / immunology
Germinal Center / immunology
Humans
Immunity, Cellular*
Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein / immunology
Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Strongyloides ratti / immunology
Strongyloides ratti / pathogenicity
Strongyloidiasis / immunology*
Strongyloidiasis / parasitology
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Th2 Cells / immunology*
Transcriptome / immunology

Substances

GATA3 Transcription Factor
Gata3 protein, mouse
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Rbpj protein, mouse