Bach2 maintains T cells in a naive state by suppressing effector memory-related genes

The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (−/−) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2−/− naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2−/− naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells.

[1]  K. Itoh,et al.  Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site , 1996, Molecular and cellular biology.

[2]  L. Madisen,et al.  Identification of Bach2 as a B‐cell‐specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3′ enhancer , 1998, The EMBO journal.

[3]  J. Inazawa,et al.  Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15 , 2000, Oncogene.

[4]  M. Groudine,et al.  Activation of β-major globin gene transcription is associated with recruitment of NF-E2 to the β-globin LCR and gene promoter , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Liming Yang,et al.  Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. , 2002, Immunity.

[6]  Satoru Takahashi,et al.  The transcriptional programme of antibody class switching involves the repressor Bach2 , 2004, Nature.

[7]  Hiroshi Suzuki,et al.  Repression of PML Nuclear Body-Associated Transcription by Oxidative Stress-Activated Bach2 , 2004, Molecular and Cellular Biology.

[8]  W. Kaelin,et al.  Proline hydroxylation and gene expression. , 2005, Annual review of biochemistry.

[9]  J. Kuźnicki,et al.  Calcyclin (S100A6) expression is stimulated by agents evoking oxidative stress via the antioxidant response element. , 2005, Biochimica et biophysica acta.

[10]  C. Benoist,et al.  A Shared Gene-Expression Signature in Innate-Like Lymphocytes. , 2005 .

[11]  Tetsuya Yamagata,et al.  A shared gene‐expression signature in innate‐like lymphocytes , 2006, Immunological reviews.

[12]  K. Igarashi,et al.  The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. , 2006, Antioxidants & redox signaling.

[13]  Masayuki Yamamoto,et al.  Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. , 2006, The Journal of clinical investigation.

[14]  R. Tooze,et al.  BLIMP‐1 is a target of cellular stress and downstream of the unfolded protein response , 2006, European journal of immunology.

[15]  P. Schwartzberg,et al.  Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk. , 2006, Immunity.

[16]  Corey M. Carlson,et al.  Kruppel-like factor 2 regulates thymocyte and T-cell migration , 2006, Nature.

[17]  L. Atherly,et al.  The Tec family tyrosine kinases Itk and Rlk regulate the development of conventional CD8+ T cells. , 2006, Immunity.

[18]  K. Calame,et al.  Transcriptional repressor Blimp-1 regulates T cell homeostasis and function , 2006, Nature Immunology.

[19]  M. Kaplan,et al.  Thymic selection pathway regulates the effector function of CD4 T cells , 2007, The Journal of experimental medicine.

[20]  K. Calame,et al.  Blimp-1 Attenuates Th1 Differentiation by Repression of ifng, tbx21, and bcl6 Gene Expression , 2008, The Journal of Immunology.

[21]  E. Sebzda,et al.  Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns , 2008, Nature Immunology.

[22]  Vincent Plagnol,et al.  Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci , 2008, Nature Genetics.

[23]  Jessica M. Lindvall,et al.  Transcriptional signatures of Itk-deficient CD3+, CD4+ and CD8+ T-cells , 2009, BMC Genomics.

[24]  Daniel R. Beisner,et al.  Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor , 2009, Nature Immunology.

[25]  S. Nutt,et al.  Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses. , 2009, Immunity.

[26]  D. Foell,et al.  The endogenous Toll–like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer , 2009, Journal of leukocyte biology.

[27]  Frederick P. Roth,et al.  Next generation software for functional trend analysis , 2009, Bioinform..

[28]  J. Thierry-Mieg,et al.  Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. , 2009, Immunity.

[29]  Masayuki Yamamoto,et al.  Structural Basis of Alternative DNA Recognition by Maf Transcription Factors , 2009, Molecular and Cellular Biology.

[30]  S. Crotty,et al.  Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation , 2010, Nature Immunology.

[31]  W. Paul,et al.  Mechanisms Underlying Lineage Commitment and Plasticity of Helper CD4+ T Cells , 2010, Science.

[32]  David J. Arenillas,et al.  Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis , 2010, Nucleic acids research.

[33]  P. Deloukas,et al.  Multiple common variants for celiac disease influencing immune gene expression , 2010, Nature Genetics.

[34]  Daniel R. Beisner,et al.  Foxo transcription factors control regulatory T cell development and function. , 2010, Immunity.

[35]  Carolyn L. Geczy,et al.  Inflammation-associated S100 proteins: new mechanisms that regulate function , 2011, Amino Acids.

[36]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[37]  G. Sykiotis,et al.  Stress-Activated Cap'n'collar Transcription Factors in Aging and Human Disease , 2010, Science Signaling.

[38]  S. Jameson,et al.  T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells , 2010, Nature Immunology.

[39]  W. Paul,et al.  Peripheral CD4+ T‐cell differentiation regulated by networks of cytokines and transcription factors , 2010, Immunological reviews.

[40]  M. Soares,et al.  Mechanisms of cell protection by heme oxygenase-1. , 2010, Annual review of pharmacology and toxicology.

[41]  K. Calame,et al.  Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch , 2010, The EMBO journal.

[42]  Masayuki Yamamoto,et al.  Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution , 2011, Genes to cells : devoted to molecular & cellular mechanisms.

[43]  Simon C. Potter,et al.  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis , 2011, Nature.

[44]  M. Ikeda-Saito,et al.  Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2. , 2011, Blood.

[45]  J. Colgan,et al.  NFIL3/E4BP4 controls type 2 T helper cell cytokine expression , 2011, The EMBO journal.

[46]  M. Jenkins,et al.  Origins of CD4+ effector and central memory T cells , 2011, Nature Immunology.

[47]  S. Jameson,et al.  Alternative memory in the CD8 T cell lineage. , 2011, Trends in immunology.

[48]  C. Klaassen,et al.  Th2 Skewing by Activation of Nrf2 in CD4+ T Cells , 2012, The Journal of Immunology.

[49]  Cheong-Hee Chang,et al.  Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections. , 2012, Open journal of immunology.

[50]  L. Picker,et al.  Hidden Memories: Frontline Memory T Cells and Early Pathogen Interception , 2012, The Journal of Immunology.

[51]  T. Kurosaki,et al.  Repression of the transcription factor Bach2 contributes to predisposition of IgG1 memory B cells toward plasma cell differentiation. , 2013, Immunity.