1. 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
- Author
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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, 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 ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
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 - Abstract
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.
- Published
- 2008
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