BATF is Required for Treg Homeostasis and Stability to Prevent Autoimmune Pathology

Regulatory T (Treg) cells are inevitable to prevent deleterious immune responses to self and commensal microorganisms. Treg function requires continuous expression of the transcription factor (TF) FOXP3 and is divided into two major subsets: resting (rTregs) and activated (aTregs). Continuous T cell receptor (TCR) signaling plays a vital role in the differentiation of aTregs from their resting state, and in their immune homeostasis. The process by which Tregs differentiate, adapt tissue specificity, and maintain stable phenotypic expression at the transcriptional level is still inconclusivei. In this work, the role of BATF is investigated, which is induced in response to TCR stimulation in naïve T cells and during aTreg differentiation. Mice lacking BATF in Tregs developed multiorgan autoimmune pathology. As a transcriptional regulator, BATF is required for Treg differentiation, homeostasis, and stabilization of FOXP3 expression in different lymphoid and non-lymphoid tissues. Epigenetically, BATF showed direct regulation of Treg-specific genes involved in differentiation, maturation, and tissue accumulation. Most importantly, FOXP3 expression and Treg stability require continuous BATF expression in Tregs, as it regulates demethylation and accessibility of the CNS2 region of the Foxp3 locus. Considering its role in Treg stability, BATF should be considered an important therapeutic target in autoimmune disease.

[1]  C. Leslie,et al.  The Transcription Factor Foxp3 Shapes Regulatory T Cell Identity by Tuning the Activity of trans-Acting Intermediaries. , 2020, Immunity.

[2]  E. Crestani,et al.  Regulatory T Cell-Derived TGF-β1 Controls Multiple Checkpoints Governing Allergy and Autoimmunity. , 2020, Immunity.

[3]  S. Zheng,et al.  The progress and prospect of regulatory T cells in autoimmune diseases. , 2020, Journal of autoimmunity.

[4]  André F. Rendeiro,et al.  Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF , 2020, Immunity.

[5]  J. Bluestone,et al.  Treg cell-based therapies: challenges and perspectives , 2019, Nature Reviews Immunology.

[6]  R. Myers,et al.  Batf Pioneers the Reorganization of Chromatin in Developing Effector T Cells via Ets1-Dependent Recruitment of Ctcf , 2019, Cell reports.

[7]  A. Rao,et al.  Loss of TET2 and TET3 in regulatory T cells unleashes effector function , 2019, Nature Communications.

[8]  A. Yoshimura,et al.  Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression. , 2019, International immunology.

[9]  T. Schoeb,et al.  Cutting Edge: ICOS-Deficient Regulatory T Cells Display Normal Induction of Il10 but Readily Downregulate Expression of Foxp3 , 2019, The Journal of Immunology.

[10]  Ricardo J. Miragaia,et al.  Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation , 2019, Immunity.

[11]  Bertrand Z. Yeung,et al.  Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics , 2018, Genome Biology.

[12]  N. Arakaki,et al.  JunB regulates homeostasis and suppressive functions of effector regulatory T cells , 2018, Nature Communications.

[13]  D. Hafler,et al.  Regulatory T cells in autoimmune disease , 2018, Nature Immunology.

[14]  Wei Zhang,et al.  Reciprocal Expression of IL-35 and IL-10 Defines Two Distinct Effector Treg Subsets that Are Required for Maintenance of Immune Tolerance. , 2017, Cell reports.

[15]  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.

[16]  Ryuichi Murakami,et al.  Analyses of a Mutant Foxp3 Allele Reveal BATF as a Critical Transcription Factor in the Differentiation and Accumulation of Tissue Regulatory T Cells , 2017, Immunity.

[17]  G. Hildebrandt,et al.  Advances in the Use of Regulatory T-Cells for the Prevention and Therapy of Graft-vs.-Host Disease , 2017, Biomedicines.

[18]  M. Kaplan,et al.  Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation. , 2017, Molecular cell.

[19]  Richard Bonneau,et al.  Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation , 2017, Nature Immunology.

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

[21]  Mi Hye Song,et al.  DNA Demethylation of the Foxp3 Enhancer Is Maintained through Modulation of Ten-Eleven-Translocation and DNA Methyltransferases , 2016, Molecules and cells.

[22]  A. Rudensky,et al.  T cell receptor signalling in the control of regulatory T cell differentiation and function , 2016, Nature Reviews Immunology.

[23]  Harri Lähdesmäki,et al.  Control of Foxp3 stability through modulation of TET activity , 2016, The Journal of experimental medicine.

[24]  A. Toure,et al.  Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity , 2016, Nature.

[25]  J. Bluestone,et al.  Targeting Treg signaling for the treatment of autoimmune diseases. , 2015, Current opinion in immunology.

[26]  Liza Konnikova,et al.  Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells , 2015, Science.

[27]  J. McMurray,et al.  Batf is important for IL-4 expression in T follicular helper cells , 2015, Nature Communications.

[28]  A. Regev,et al.  Spatial reconstruction of single-cell gene expression , 2015, Nature Biotechnology.

[29]  Marco Y. Hein,et al.  Continuous T cell receptor signals maintain a functional regulatory T cell pool. , 2014, Immunity.

[30]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[31]  A. Rudensky,et al.  Continuous requirement for the T cell receptor for regulatory T cell function , 2014, Nature Immunology.

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

[33]  C. Benner,et al.  Function of a Foxp3 cis-Element in Protecting Regulatory T Cell Identity , 2014, Cell.

[34]  A. Regev,et al.  The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells , 2014, Nature Immunology.

[35]  Adrian Liston,et al.  Homeostatic control of regulatory T cell diversity , 2014, Nature Reviews Immunology.

[36]  D. Campbell,et al.  CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets , 2014, The Journal of experimental medicine.

[37]  K. Murphy,et al.  Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks , 2013, Nature Reviews Immunology.

[38]  B. Zheng,et al.  TNF-α impairs differentiation and function of TGF-β-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway. , 2013, Journal of molecular cell biology.

[39]  S. Sakaguchi,et al.  Development and maintenance of regulatory T cells. , 2013, Immunity.

[40]  S. Nutt,et al.  Differentiation and function of Foxp3(+) effector regulatory T cells. , 2013, Trends in immunology.

[41]  K. Nakai,et al.  T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. , 2012, Immunity.

[42]  Michael Q. Zhang,et al.  Novel Foxo1-dependent transcriptional programs control Treg cell function , 2012, Nature.

[43]  Richard Bonneau,et al.  A Validated Regulatory Network for Th17 Cell Specification , 2012, Cell.

[44]  Scott A. Shaffer,et al.  Transcription factor Foxp3 and its protein partners form a complex regulatory network , 2012, Nature Immunology.

[45]  Y. Wan,et al.  An essential role of the transcription factor GATA-3 for the function of regulatory T cells. , 2011, Immunity.

[46]  J. Myśliwska,et al.  Anti-TNF rescue CD4+Foxp3+ regulatory T cells in patients with type 1 diabetes from effects mediated by TNF. , 2011, Cytokine.

[47]  K. Sakimura,et al.  Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression , 2011, Proceedings of the National Academy of Sciences.

[48]  Kenneth M. Murphy,et al.  Batf controls the global regulators of class switch recombination in both B and T cells , 2011, Nature Immunology.

[49]  L. Olson,et al.  The Ets-1 transcription factor controls the development and function of natural regulatory T cells , 2010, The Journal of experimental medicine.

[50]  Christophe Benoist,et al.  Stability of the Regulatory T Cell Lineage in Vivo , 2010, Science.

[51]  R. Baumgrass,et al.  Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells , 2010, Journal of Molecular Medicine.

[52]  E. Taparowsky,et al.  Batf coordinates multiple aspects of B and T cell function required for normal antibody responses , 2010, The Journal of experimental medicine.

[53]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[54]  A. Rudensky,et al.  Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate , 2010, Nature.

[55]  T. Nomura,et al.  Indispensable role of the Runx1-Cbfbeta transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells. , 2009, Immunity.

[56]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[57]  Gary D. Stormo,et al.  The AP-1 transcription factor Batf controls TH17 differentiation , 2009, Nature.

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

[59]  T. Nomura,et al.  CTLA-4 Control over Foxp3+ Regulatory T Cell Function , 2008, Science.

[60]  Clifford A. Meyer,et al.  Model-based Analysis of ChIP-Seq (MACS) , 2008, Genome Biology.

[61]  Xiaomin Song,et al.  TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3 , 2008, Proceedings of the National Academy of Sciences.

[62]  T. Nomura,et al.  Regulatory T Cells and Immune Tolerance , 2008, Cell.

[63]  L. Luo,et al.  A global double‐fluorescent Cre reporter mouse , 2007, Genesis.

[64]  W. Leonard,et al.  CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation , 2007, The Journal of experimental medicine.

[65]  A. Rudensky,et al.  Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3 , 2007, Nature Immunology.

[66]  R. Andreesen,et al.  Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. , 2006, Blood.

[67]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[68]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2003 .

[69]  R Kuhn,et al.  Temporally and spatially regulated somatic mutagenesis in mice. , 1998, Nucleic acids research.

[70]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[71]  P. Chambon,et al.  Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[72]  H. Ochs,et al.  The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 , 2001, Nature Genetics.

[73]  D. Galas,et al.  Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse , 2001, Nature Genetics.