title: Nck adaptor proteins modulate differentiation and effector function of T cells.
abstract: Understanding the molecular mechanisms regulating T cell reactivity is required for successful reprogramming of immune responses in medical conditions, characterized by dysfunctions of the immune system. Nck proteins are cytoplasmic adaptors mediating diverse cellular functions, including TCR signaling. By enhancing TCR signal strength, Nck proteins influence thymic selection and regulate the size and sensitivity of the peripheral T cell repertoire. Here, we investigated the contribution of Nck proteins to CD4(+) T cell differentiation and effector function using Nck.T(-/-) mice. Impaired GC formation and reduced Tfh were observed in Nck.T(-/-) mice after immunization with T cell-dependent antigens. Th2/Tfh-related cytokines, such as IL-4, IL-10, and IL-21, were decreased in Nck.T(-/-) mice T cells. Moreover, an increased susceptibility to cell death of Tfh cells in Nck.T(-/-) mice was associated with decreased levels of Akt phosphorylation. As a result of this dysregulation in Tfh cells of Nck.T(-/-) mice, we found impaired production and affinity maturation of antibodies against T cell-dependent antigens. Thus, Nck proteins not only participate in thymic selection and generation of the peripheral T cell repertoire but also are involved in the differentiation and effector functions of CD4(+) T cells.
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kun-Hui
authors.initials: KH
authors.lastname: Lu
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Selina
authors.initials: S
authors.lastname: Keppler
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Torsten
authors.initials: T
authors.lastname: Mattfeldt
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Angelo
authors.initials: A
authors.lastname: Castello
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kostezka
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Günter
authors.initials: G
authors.lastname: Küblbeck
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Klevenz
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Prokosch
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Georg
authors.initials: G
authors.lastname: Pougialis
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Facundo
authors.initials: F
authors.lastname: Batista
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Tafuri
authors.affiliation: *Molecular Immunology, German Cancer Research Center, Heidelberg, Germany; Lymphocyte Interaction Laboratory, London Research Institute-Cancer Research UK, London, United Kingdom; Department of Pathology, Universitätsklinikum, Ulm, Germany; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada b.arnold@dkfz.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D017353:Gene Deletion; D018858:Germinal Center / Q000166:cytology; D006801:Humans; D051379:Mice; D015513:Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C078332:Nck protein; D015513:Oncogene Proteins; D014157:Transcription Factors
keywords: Tfh; antibody production; cell death; follicular helper T; germinal center