Th2 Lymphoproliferative Disorder of Lat super(Y136F) Mutant Mice Unfolds Independently of TCR-MHC Engagement and Is Insensitive to the Action of Foxp3 super(+) Regulatory T Cells

Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat super(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 auto...

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Published in:The Journal of immunology (1950) 2008-02, Vol.180 (3), p.1565-1575
Main Authors: Wang, Ying, Kissenpfennig, Adrien, Mingueneau, Michael, Richelme, Sylvie, Perrin, Pierre, Chevrier, Stephane, Genton, Celine, Lucas, Bruno, DiSanto, James P, Acha-Orbea, Hans, Malissen, Bernard, Malissen, Marie
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Language:English
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Summary:Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat super(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 super(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 super(Y136F) CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3 super(+) regulatory T cells are present in Lat super(Y136F) mice and that pathogenic Lat super(Y136F) CD4 T cells were capable of escaping the control of infused wild-type Foxp3 super(+) regulatory T cells. These results argue against a scenario where the Lat super(Y136F) pathology is primarily due to a lack of functional Foxp3 super(+) regulatory T cells and suggest that a defect intrinsic to Lat super(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat super(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 super(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.
ISSN:0022-1767