The NF-κB transcription factor RelA is required for the tolerogenic function of Foxp3(+) regulatory T cells

Nicole Messina; Thomas Fulford; Lorraine O'Reilly; Wen Xian Loh; Jessica M Motyer; Darcy Ellis; Catriona McLean; Haroon Naeem; Ann Lin; Raffi Gugasyan; Robyn M Slattery; Raelene J Grumont; Steve Gerondakis

doi:10.1016/j.jaut.2016.03.017

The NF-κB transcription factor RelA is required for the tolerogenic function of Foxp3(+) regulatory T cells

J Autoimmun. 2016 Jun:70:52-62. doi: 10.1016/j.jaut.2016.03.017. Epub 2016 Apr 7.

Authors

Affiliations

¹ Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
² Walter and Eliza Hall Institute of Medical Research, 1G, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050, Australia.
³ Department of Immunology, Monash University Central Clinical School, Prahran, Victoria 3004, Australia.
⁴ Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
⁵ Department of Anatomical Pathology, The Alfred Hospital, Prahran, Victoria 3004, Australia.
⁶ Monash Bioinformatics Platform, Monash University, Clayton, Victoria 3800, Australia.
⁷ Walter and Eliza Hall Institute of Medical Research, 1G, Parkville, Victoria 3052, Australia.
⁸ The Burnet Institute, Prahran, Victoria 3004, Australia.
⁹ Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. Electronic address: steven.gerondakis@monash.edu.

PMID: 27068879
DOI: 10.1016/j.jaut.2016.03.017

Abstract

The properties of CD4(+) regulatory T cell (Treg) subsets are dictated by distinct patterns of gene expression determined by FOXP3 and different combinations of various transcription factors. Here we show the NF-κB transcription factor RelA is constitutively active in naïve and effector Tregs. The conditional inactivation of Rela in murine FOXP3(+) cells induces a rapid onset, multi-focal autoimmune disease that depends on RelA being expressed in conventional T cells. In addition to promoting Treg lineage stability, RelA determines the size of the effector Treg population, a function influenced by the presence or absence of RelA in conventional T cells. These findings showing that RelA controls Treg stability and promotes the competitive fitness of effector Tregs highlight the importance of RelA activity in peripheral Treg induced tolerance.

Keywords: Autoimmune disease; Conditional gene targeting; Nuclear factor of kappaB; Regulatory T cells; RelA.

Publication types

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

MeSH terms

Animals
Antibodies / blood
Antibodies / immunology
Autoimmune Diseases / genetics
Autoimmune Diseases / immunology
Autoimmune Diseases / metabolism
Autoimmune Diseases / pathology
Autoimmunity
Biomarkers
Cluster Analysis
Cytokines / blood
Cytokines / metabolism
Disease Models, Animal
Female
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Profiling
Immune Tolerance* / genetics
Immunomodulation
Immunophenotyping
Lymphocyte Activation / genetics
Lymphocyte Activation / immunology
Lymphocyte Count
Male
Mice
Mice, Transgenic
Phenotype
T-Lymphocyte Subsets / immunology
T-Lymphocyte Subsets / metabolism
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism*
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism*

Substances

Antibodies
Biomarkers
Cytokines
Forkhead Transcription Factors
Foxp3 protein, mouse
Transcription Factor RelA