Article: article from journal or magazin.
Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.
Journal of Immunology
Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat(Y136F) 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 Lat(Y136F) 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 Lat(Y136F) 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 Lat(Y136F) mice and that pathogenic Lat(Y136F) 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 Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat(Y136F) 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 Lat(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.
Adaptor Proteins, Signal Transducing/genetics, Animals, Antigens, CD4/analysis, Autoantibodies/blood, Autoimmune Diseases/genetics, Autoimmune Diseases/immunology, Cell Proliferation, Forkhead Transcription Factors/analysis, Forkhead Transcription Factors/genetics, Green Fluorescent Proteins/analysis, Green Fluorescent Proteins/genetics, Histocompatibility Antigens Class II/immunology, Interleukin-7/metabolism, Lymphoproliferative Disorders/genetics, Lymphoproliferative Disorders/immunology, Membrane Proteins/genetics, Mice, Mice, Mutant Strains, Phosphoproteins/genetics, Receptors, Antigen, T-Cell/immunology, T-Lymphocytes, Regulatory/immunology, Th2 Cells/immunology
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