T-bet deficiency decreases susceptibility to experimental myasthenia gravis.
T-bet, a tissue-specific transcription factor, controls T helper 1 (Th1) cell differentiation and IFN-production. Given the reciprocal relationship between Th1 and other types of helper T cells, we hypothesized that T-bet impacts multiple helper and regulatory T (Treg) cells, thereby influencing the magnitude of autoimmune disease. We tested this hypothesis in an experimental model of autoimmune myasthenia gravis (EAMG) of mice. Myasthenia gravis (MG) and EAMG are T cell-driven, IgG autoantibody-mediated disorders that destroy muscles by attacking the target antigen acetylcholine receptor (AChR) or other antigens of skeletal muscle at neuromuscular junctions. We show that, compared to wild-type mice, AChR-primed T-bet(-/-) mice are less susceptible to EAMG. This phenotype is associated with a reduction of autoreactive Th1 cells and augmentation of Th2 and Th17 cells as well as an upregulation of Foxp3 expression by T-bet(-/-)CD4(+)CD25(+) Treg cells. Thus, in our model, T-bet not only specifies the Th1 lineage but also has a broad influence on autoreactive Th2, Th17 and Treg cells. These coordinated effects reduce the genesis of pathogenic antibodies and protect against B cell-mediated EAMG.
Liu
Ruolan
R
Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 W Thomas Road, Phoenix, AZ 85013-4496, USA. Ruolan.Liu@chw.edu
Hao
Junwei
J
Dayao
Carlos S
CS
Shi
Fu-Dong
FD
Campagnolo
Denise I
DI
D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D015704:CD4 Antigens / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000096:biosynthesis / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
D000963:Antimetabolites; D015704:CD4 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D011950:Receptors, Cholinergic; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D001973:Bromodeoxyuridine