title: Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex.
abstract: Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expression of genes in the TH2 subset of helper T cells to enhancer occupancy by the BATF-IRF4 transcription factor complex at varying strengths of TCR stimulation. Genes dependent on BATF-IRF4 clustered into groups with distinct TCR sensitivities. Enhancers exhibited a spectrum of occupancy by the BATF-IRF4 ternary complex that correlated with the sensitivity of gene expression to TCR signal strength. DNA sequences immediately flanking the previously defined AICE motif controlled the affinity of BATF-IRF4 for direct binding to DNA. Analysis by the chromatin immunoprecipitation-exonuclease (ChIP-exo) method allowed the identification of a previously unknown high-affinity AICE2 motif at a human single-nucleotide polymorphism (SNP) of the gene encoding the immunomodulatory receptor CTLA-4 that was associated with resistance to autoimmunity. Thus, the affinity of different enhancers for the BATF-IRF4 complex might underlie divergent signaling outcomes in response to various strengths of TCR signaling.
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Arifumi
authors.initials: A
authors.lastname: Iwata
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Durai
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Roxane
authors.initials: R
authors.lastname: Tussiwand
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Briseño
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Grajales-Reyes
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Takeshi
authors.identifier: 0000-0001-7489-1051
authors.initials: T
authors.lastname: Egawa
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.|Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D018418:Th2 Cells / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D060908:CTLA-4 Antigen; D050835:Interferon Regulatory Factors; D046912:Multiprotein Complexes; D011948:Receptors, Antigen, T-Cell; D000099218:Interferon Regulatory Factor-4; C431772:Batf protein, mouse