title: Lunatic, Manic, and Radical Fringe Each Promote T and B Cell Development.
abstract: Lunatic, Manic, and Radical Fringe (LFNG, MFNG, and RFNG) are N-acetylglucosaminyltransferases that modify Notch receptors and regulate Notch signaling. Loss of LFNG affects thymic T cell development, and LFNG and MFNG are required for marginal zone (MZ) B cell development. However, roles for MFNG and RFNG in T cell development, RFNG in B cell development, or Fringes in T and B cell activation are not identified. In this study, we show that Lfng/Mfng/Rfng triple knockout (Fng tKO) mice exhibited reduced binding of DLL4 Notch ligand to CD4/CD8 double-negative (DN) T cell progenitors, and reduced expression of NOTCH1 targets Deltex1 and CD25. Fng tKO mice had reduced frequencies of DN1/cKit(+) and DN2 T cell progenitors and CD4(+)CD8(+) double-positive (DP) T cell precursors, but increased frequencies of CD4(+) and CD8(+) single-positive T cells in the thymus. In spleen, Fng tKO mice had reduced frequencies of CD4(+), CD8(+), central memory T cells and MZ B cells, and an increased frequency of effector memory T cells, neutrophils, follicular, and MZ P B cells. The Fng tKO phenotype was cell-autonomous and largely rescued in mice expressing one allele of a single Fng gene. Stimulation of Fng tKO splenocytes with anti-CD3/CD28 beads or LPS gave reduced proliferation compared with controls, and the generation of activated T cells by Concanavalin A or L-PHA was also reduced in Fng tKO mice. Therefore, each Fringe contributes to T and B cell development, and Fringe is required for optimal in vitro stimulation of T and B cells.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461.
authors.forename: Hua-Xing
authors.identifier: http://orcid.org/0000-0003-3062-0879
authors.initials: HX
authors.lastname: Wei
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461.
authors.forename: Ju
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461 pamela.stanley@einstein.yu.edu.
authors.forename: Pamela
authors.identifier: http://orcid.org/0000-0001-5704-3747
authors.initials: P
authors.lastname: Stanley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D003208:Concanavalin A / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000276:immunology; D005964:Glucosyltransferases; D016695:Glycosyltransferases / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072101:Jagged-2 Protein; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000276:immunology; D051883:Receptor, Notch2 / Q000096:biosynthesis / Q000276:immunology; D000072099:Serrate-Jagged Proteins; D013950:Thymus Gland / Q000166:cytology; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D011506:Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins; D003208:Concanavalin A; C104035:Dtx1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D016695:Glycosyltransferases; D005964:Glucosyltransferases; C498392:Lfng protein, mouse; C486343:Mfng protein, mouse; C491317:Rfng protein, mouse