Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.
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.
Wang
Ying
Y
Centre d'Immunologie de Marseille-Luminy, INSERM/CNRS, Université de la Méditerranée, Parc Scientifique et Technologique de Luminy, Marseille Cedex 09, France.
Kissenpfennig
Adrien
A
Mingueneau
Michael
M
Richelme
Sylvie
S
Perrin
Pierre
P
Chevrier
Stéphane
S
Genton
Céline
C
Lucas
Bruno
B
DiSanto
James P
JP
Acha-Orbea
Hans
H
Malissen
Bernard
B
Malissen
Marie
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D015851:Interleukin-7 / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D015851:Interleukin-7; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins