title: Themis2 lowers the threshold for B cell activation during positive selection.
abstract: The positive and negative selection of lymphocytes by antigen is central to adaptive immunity and self-tolerance, yet how this is determined by different antigens is not completely understood. We found that thymocyte-selection-associated family member 2 (Themis2) increased the positive selection of B1 cells and germinal center B cells by self and foreign antigens. Themis2 lowered the threshold for B-cell activation by low-avidity, but not high-avidity, antigens. Themis2 constitutively bound the adaptor protein Grb2, src-kinase Lyn and signal transducer phospholipase γ2 (PLC-γ2), and increased activation of PLC-γ2 and its downstream pathways following B cell receptor stimulation. Our findings identify a unique function for Themis2 in differential signaling and provide insight into how B cells discriminate between antigens of different quantity and quality.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Daian
authors.initials: D
authors.lastname: Cheng
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Mukta
authors.initials: M
authors.lastname: Deobagkar-Lele
authors.affiliation: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Zvezdova
authors.affiliation: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Seeyoung
authors.initials: S
authors.lastname: Choi
authors.affiliation: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Uehara
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Baup
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Sophia C
authors.initials: SC
authors.lastname: Bennett
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Bull
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Crockford
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ferry
authors.affiliation: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Warzecha
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale and Université de Toulouse, Université Paul Sabatier, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Marcellin
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale and Université de Toulouse, Université Paul Sabatier, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Anne Gonzalez
authors.initials: AG
authors.lastname: de Peredo
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; and Institut National de la Santé et de la Recherche Médicale, U1043, Centre National de la Recherche Scientifique, and Université de Toulouse, Université Paul Sabatier, Toulouse, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Lesourne
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Anzilotti
authors.affiliation: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Love
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D060966:Clonal Selection, Antigen-Mediated; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051966:Phospholipase C gamma / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017634:Self Tolerance; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; C575530:Themis2 protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051966:Phospholipase C gamma