title: The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells.
abstract: The transcription factor BATF is required for the differentiation of interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and follicular helper T cells (TFH cells). Here we identified a fundamental role for BATF in regulating the differentiation of effector of CD8(+) T cells. BATF-deficient CD8(+) T cells showed profound defects in effector population expansion and underwent proliferative and metabolic catastrophe early after encountering antigen. BATF, together with the transcription factors IRF4 and Jun proteins, bound to and promoted early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies T cell antigen receptor (TCR)-dependent expression of transcription factors and augments the propagation of inflammatory signals but restrains the expression of genes encoding effector molecules. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved.
authors.affiliation: 1] Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [2] Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [3].
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurachi
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2].
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Barnitz
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Yosef
authors.affiliation: 1] Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [2] Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Odorizzi
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: DiIorio
authors.affiliation: Bioinfo, Plantagenet, Canada.
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Yates
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jernej
authors.initials: J
authors.lastname: Godec
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Klatt
authors.affiliation: 1] Bioinfo, Plantagenet, Canada. [2] Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: 1] Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [2] Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. [3].
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [4].
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D053804:Granzymes; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016755:Proto-Oncogene Proteins c-jun; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4; C431772:Batf protein, mouse; C513258:Prdm1 protein, mouse