Th2 Lymphoproliferative Disorder of Lat Y136F Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3+ Regulatory T Cells
| Autor: | Céline Genton, Adrien Kissenpfennig, Michael Mingueneau, Hans Acha-Orbea, Marie Malissen, Sylvie Richelme, Ying Wang, Pierre Perrin, Stéphane Chevrier, Bruno Lucas, James P. DiSanto, Bernard Malissen |
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| Přispěvatelé: | Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Cytokines et Développement Lymphoïde, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Biochemistry, Université de Lausanne ( UNIL ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU) |
| Rok vydání: | 2008 |
| Předmět: |
Adoptive cell transfer
MESH: Mice Mutant Strains MESH: Antigens CD4 MESH : Green Fluorescent Proteins T-Lymphocytes Regulatory MESH : Receptors Antigen T-Cell MESH : T-Lymphocytes Regulatory Mice MESH: Lymphoproliferative Disorders 0302 clinical medicine MESH: Autoimmune Diseases MESH : Cell Proliferation [ SDV.IMM ] Life Sciences [q-bio]/Immunology MESH: Autoantibodies Immunology and Allergy MESH: Animals MESH : Adaptor Proteins Signal Transducing 0303 health sciences MESH : Lymphoproliferative Disorders biology FOXP3 Forkhead Transcription Factors MESH: Receptors Antigen T-Cell 3. Good health MESH : Forkhead Transcription Factors MESH : Histocompatibility Antigens Class II CD4 Antigens [SDV.IMM]Life Sciences [q-bio]/Immunology MESH: Membrane Proteins MESH : Interleukin-7 Green Fluorescent Proteins Immunology Receptors Antigen T-Cell Linker for Activation of T cells Major histocompatibility complex MESH: Phosphoproteins Autoimmune Diseases 03 medical and health sciences MESH : Autoimmune Diseases Th2 Cells MESH: Green Fluorescent Proteins Antigen MESH: Forkhead Transcription Factors MESH: Th2 Cells MESH : Autoantibodies MESH: Cell Proliferation MESH : Mice MHC class I Animals MESH: Mice Adaptor Proteins Signal Transducing Autoantibodies Cell Proliferation MESH: Adaptor Proteins Signal Transducing 030304 developmental biology Interleukin-7 MESH: T-Lymphocytes Regulatory T-cell receptor Histocompatibility Antigens Class II Autoantibody Membrane Proteins Phosphoproteins Molecular biology Lymphoproliferative Disorders Mice Mutant Strains MESH: Interleukin-7 MESH : Th2 Cells MESH : Mice Mutant Strains MESH : Membrane Proteins MESH: Histocompatibility Antigens Class II biology.protein MESH : Antigens CD4 MESH : Animals MESH : Phosphoproteins 030215 immunology |
| Zdroj: | Journal of Immunology Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2008, 180 (3), pp.1565-75. ⟨10.4049/jimmunol.180.3.1565⟩ Journal of Immunology, 2008, 180 (3), pp.1565-75. ⟨10.4049/jimmunol.180.3.1565⟩ Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2008, 180 (3), pp.1565-75. 〈10.4049/jimmunol.180.3.1565〉 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (LatY136F mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies. We analyzed whether the LatY136F pathology constitutes a bona fide autoimmune disorder dependent on TCR specificity. Using adoptive transfer experiments, we demonstrated that the expansion and uncontrolled Th2-effector function of LatY136F CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3+ regulatory T cells are present in LatY136F mice and that pathogenic LatY136F CD4 T cells were capable of escaping the control of infused wild-type Foxp3+ regulatory T cells. These results argue against a scenario where the LatY136F pathology is primarily due to a lack of functional Foxp3+ regulatory T cells and suggest that a defect intrinsic to LatY136F CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers LatY136F CD4 T cells with the ability to trigger the production of Abs and of autoantibodies in a TCR-independent, quasi-mitogenic fashion. Therefore, despite the presence of autoantibodies causative of severe systemic disease, the pathological conditions observed in LatY136F mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder. |
| Databáze: | OpenAIRE |
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