title: Epigenetic regulation of IL-12-dependent T cell proliferation.
abstract: It is well established that the cytokine IL-12 and the transcription factor STAT4, an essential part of the IL-12 signaling pathway, are critical components of the Th1 differentiation process in T cells. In response to pathogenic stimuli, this process causes T cells to proliferate rapidly and secrete high amounts of the cytokine IFN-γ, leading to the Th1 proinflammatory phenotype. However, there are still unknown components of this differentiation pathway. We here demonstrated that the expression of the histone methyltransferase Mll1 is driven by IL-12 signaling through STAT4 in humans and mice and is critical for the proper differentiation of a naïve T cell to a Th1 cell. Once MLL1 is up-regulated by IL-12, it regulates the proliferation of Th1 cells. As evidence of this, we show that Th1 cells from Mll1(+/-) mice are unable to proliferate rapidly in a Th1 environment in vitro and in vivo. Additionally, upon restimulation with cognate antigen Mll1(+/-), T cells do not convert to a Th1 phenotype, as characterized by IFN-γ output. Furthermore, we observed a reduction in IFN-γ production and proliferation in human peripheral blood stimulated with tetanus toxoid by use of a specific inhibitor of the MLL1/menin complex. Together, our results demonstrate that the MLL1 gene plays a previously unrecognized but essential role in Th1 cell biology and furthermore, describes a novel pathway through which Mll1 expression is regulated.
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain mschalle@umich.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schaller
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Allen
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kroetz
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Kittan
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ptaschinski
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Karen
authors.initials: K
authors.lastname: Cavassani
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: William F
authors.initials: WF
authors.lastname: Carson
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Godessart
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: *Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Immunology, Nara Medical University, Nara, Japan; and Dermatology Research, Almirall, S.A., St Feliu de Llobregat, Spain.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D044127:Epigenesis, Genetic / Q000235:genetics / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D050797:STAT4 Transcription Factor; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D055815:Young Adult
chemical_list: C497422:KMT2A protein, human; D050797:STAT4 Transcription Factor; D051788:Myeloid-Lymphoid Leukemia Protein; D018664:Interleukin-12; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
keywords: STAT4; Th1 differentiation; histone methylation; trithorax