Title | Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Wang Y, Kissenpfennig A, Mingueneau M, Richelme S, Perrin P, Chevrier S, Genton C, Lucas B, DiSanto JP, Acha-Orbea H, Malissen B, Malissen M |
Journal | J Immunol |
Volume | 180 |
Issue | 3 |
Pagination | 1565-75 |
Date Published | 2008 Feb 01 |
ISSN | 0022-1767 |
Keywords | Adaptor Proteins, Signal Transducing, Animals, Autoantibodies, Autoimmune Diseases, CD4 Antigens, Cell Proliferation, Forkhead Transcription Factors, Green Fluorescent Proteins, Histocompatibility Antigens Class II, Interleukin-7, Lymphoproliferative Disorders, Membrane Proteins, Mice, Mice, Mutant Strains, Phosphoproteins, Receptors, Antigen, T-Cell, T-Lymphocytes, Regulatory, Th2 Cells |
Abstract | 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. |
Alternate Journal | J. Immunol. |
PubMed ID | 18209052 |
Submitted by kej2006 on June 6, 2018 - 4:10pm