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* Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée,
Institut National de la Santé et de la Recherche Médicale U631,
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6102, Marseille;
Department of Immunology, Cochin Institute, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, René Descartes University, Cochin Hospital,
¶ Unité des Cytokines et Dévelopement Lymphoïde, Institut Pasteur,
|| Institut National de la Santé et de la Recherche Médicale U668, Paris, France; and
# Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
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.
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1 This work was supported by Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Pasteur, Défis de la Recherche en Allergologie by Fondation pour la recherche médicale (Défis de la Recherche en Allergologie), Agence Nationale de la Recherche, Ministère de l’Education Nationale et de la Recherche (Plate-forme Réunion Inter Organisme-Marseille Nice Génopole), Association Française Contre les Myopathies, Association pour la Recherche sur le Cancer, and the European Community (MUGEN Network of Excellence LSHG-CT-2005-005203). Y.W. was supported by an exchange fellowship between Université de la Méditerranée and School of Medicine, Shanghai Jiaotong University.
2 Current address: Infection and Immunity Group, Centre for Cancer Research and Cell Biology, School of Biomedical Sciences, Queen’s University, Belfast, Northern Ireland.
3 Address correspondence and reprint requests to Dr. Bernard Malissen, Centre d’Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de la Méditerranée, Parc Scientifique et Technologique de Luminy, Case 906, 13288 Marseille Cedex 09, France. E-mail address: bernardm{at}ciml.univ-mrs.fr
4 Abbreviations used in this paper: LAT, linker for activation of T cells; ES cell, embryonic stem cell; WT, wild type.
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