The NF-κB RelA Transcription Factor Is Critical for Regulatory T Cell Activation and Stability

Regulatory T cells (Tregs) play a major role in immune homeostasis and in the prevention of autoimmune diseases. It has been shown that c-Rel is critical in Treg thymic differentiation, but little is known on the role of NF-κB on mature Treg biology. We thus generated mice with a specific knockout of RelA, a key member of NF-κB, in Tregs. These mice developed a severe autoimmune syndrome with multi-organ immune infiltration and high activation of lymphoid and myeloid cells. Phenotypic and transcriptomic analyses showed that RelA is critical in the acquisition of the effector Treg state independently of surrounding inflammatory environment. Unexpectedly, RelA-deficient Tregs also displayed reduced stability and cells that had lost Foxp3 produced inflammatory cytokines. Overall, we show that RelA is critical for Treg biology as it promotes both the generation of their effector phenotype and the maintenance of their identity.

[1]  R. Rad,et al.  Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation , 2019, Cell reports.

[2]  Allon M Klein,et al.  Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR , 2018, Nature Immunology.

[3]  Liang Zhou,et al.  The Aryl Hydrocarbon Receptor Preferentially Marks and Promotes Gut Regulatory T Cells. , 2017, Cell reports.

[4]  Jonathan L. Schmid-Burgk,et al.  Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells. , 2017, Cell reports.

[5]  R. Rabadán,et al.  An NF-κB Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function. , 2017, Immunity.

[6]  W. Shi,et al.  The TNF Receptor Superfamily-NF-κB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues. , 2017, Cell reports.

[7]  C. Benoist,et al.  Different molecular complexes that mediate transcriptional induction and repression by FoxP3 , 2017, Nature Immunology.

[8]  C. Benoist,et al.  Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity , 2017, Proceedings of the National Academy of Sciences.

[9]  W. Shi,et al.  Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb , 2017, Immunity.

[10]  C. Leslie,et al.  Memory of Inflammation in Regulatory T Cells , 2016, Cell.

[11]  Haroon Naeem,et al.  The NF-κB transcription factor RelA is required for the tolerogenic function of Foxp3(+) regulatory T cells. , 2016, Journal of autoimmunity.

[12]  E. Zandi,et al.  Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis. , 2015, Immunity.

[13]  A. Enk,et al.  Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease , 2015, Arthritis Research & Therapy.

[14]  J. Bluestone,et al.  The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. , 2015, Immunity.

[15]  Xueqiang Wu,et al.  IKKα is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  P. Cole,et al.  Two Histone/Protein Acetyltransferases, CBP and p300, Are Indispensable for Foxp3+ T-Regulatory Cell Development and Function , 2014, Molecular and Cellular Biology.

[17]  A. Rudensky,et al.  Control of the Inheritance of Regulatory T Cell Identity by a cis Element in the Foxp3 Locus , 2014, Cell.

[18]  P. Coffer,et al.  Post-translational modification networks regulating FOXP3 function. , 2014, Trends in immunology.

[19]  A. Hoffmann,et al.  Analysis of the RelA:CBP/p300 Interaction Reveals Its Involvement in NF-κB-Driven Transcription , 2013, PLoS biology.

[20]  B. Malissen,et al.  Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells , 2013, Nature Communications.

[21]  V. Baud,et al.  RelB inhibits cell proliferation and tumor growth through p53 transcriptional activation , 2013, Oncogene.

[22]  F. Marincola,et al.  BACH2 represses effector programmes to stabilize Treg-mediated immune homeostasis - a new target in tumor immunotherapy? , 2013, Journal of Immunotherapy for Cancer.

[23]  S. Ghosh,et al.  NF‐κB: roles and regulation in different CD4+ T‐cell subsets , 2013, Immunological reviews.

[24]  S. Caristi,et al.  Forkhead Transcription Factor FOXP3 Upregulates CD25 Expression through Cooperation with RelA/NF-κB , 2012, PloS one.

[25]  C. Benoist,et al.  PPARγ is a major driver of the accumulation and phenotype of adipose-tissue Treg cells , 2012, Nature.

[26]  S. Akira,et al.  Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells , 2012, Nature Immunology.

[27]  Keji Zhao,et al.  GATA3 controls Foxp3⁺ regulatory T cell fate during inflammation in mice. , 2011, The Journal of clinical investigation.

[28]  A. Beg,et al.  The Th17 immune response is controlled by the Rel–RORγ–RORγT transcriptional axis , 2011, The Journal of experimental medicine.

[29]  Tim F. Rayner,et al.  Foxp3+ follicular regulatory T cells control T follicular helper cells and the germinal center response , 2011, Nature Medicine.

[30]  W. Shi,et al.  The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells , 2011, Nature Immunology.

[31]  S. Ghosh,et al.  NF-κB in immunobiology , 2011, Cell Research.

[32]  A. Costanzo,et al.  CD28 costimulation regulates FOXP3 in a RelA/NF‐κB‐dependent mechanism , 2011, European journal of immunology.

[33]  J. Farber,et al.  CCR6 Marks Regulatory T Cells as a Colon-Tropic, IL-10–Producing Phenotype , 2010, The Journal of Immunology.

[34]  G. Crawford,et al.  Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli. , 2010, Immunity.

[35]  S. Gerondakis,et al.  Roles of the NF-kappaB pathway in lymphocyte development and function. , 2010, Cold Spring Harbor perspectives in biology.

[36]  M. F. Shannon,et al.  c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells , 2009, The Journal of experimental medicine.

[37]  M. Greene,et al.  Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. , 2009, Immunity.

[38]  S. Ghosh,et al.  Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. , 2009, Immunity.

[39]  A. Rudensky,et al.  CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner , 2009, Science.

[40]  Michael C. Ostrowski,et al.  Eos Mediates Foxp3-Dependent Gene Silencing in CD4+ Regulatory T Cells , 2009, Science.

[41]  J. Bluestone,et al.  Foxp3 instability leads to the generation of pathogenic memory T cells in vivo , 2009, Nature immunology.

[42]  Daniel J. Campbell,et al.  T-bet controls regulatory T cell homeostasis and function during type-1 inflammation , 2009, Nature Immunology.

[43]  M. Karin,et al.  Regulation and function of NF-kappaB transcription factors in the immune system. , 2009, Annual review of immunology.

[44]  A. Rudensky,et al.  Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses , 2009, Nature.

[45]  S. Ju,et al.  Regulation of multi-organ inflammation in the regulatory T cell-deficient scurfy mice , 2009, Journal of Biomedical Science.

[46]  K. Kretschmer,et al.  DNA methylation controls Foxp3 gene expression , 2008, European journal of immunology.

[47]  E. Chi,et al.  Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. , 2008, Immunity.

[48]  P. Perrin,et al.  Th2 Lymphoproliferative Disorder of LatY136F Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3+ Regulatory T Cells1 , 2008, The Journal of Immunology.

[49]  Christophe Benoist,et al.  Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. , 2007, Immunity.

[50]  A. Rudensky,et al.  Altering the distribution of Foxp3+ regulatory T cells results in tissue-specific inflammatory disease , 2007, The Journal of experimental medicine.

[51]  D. Saur,et al.  Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis. , 2007, The Journal of clinical investigation.

[52]  T. Nomura,et al.  Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1 , 2007, Nature.

[53]  Shimon Sakaguchi,et al.  Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease , 2006, Immunological reviews.

[54]  J. Stroud,et al.  FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT , 2006, Cell.

[55]  E. Bettelli,et al.  Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[56]  P. Krammer,et al.  NF‐κB synergizes with NF‐AT and NF‐IL6 in activation of the IL‐4 gene in T cells , 2004 .

[57]  Susan M. Kaech,et al.  Molecular and Functional Profiling of Memory CD8 T Cell Differentiation , 2002, Cell.

[58]  Jing Sun,et al.  Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. , 2002, The Journal of clinical investigation.