TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation.
T cell-specific deletion of the receptor for transforming growth factor-β (TGF-β) mediated by Cre recombinase expressed early in T cell development leads to early-onset lethal autoimmune disease that cannot be controlled by regulatory T cells. However, when we deleted that receptor through the use of Cre driven by a promoter that is active much later in T cell development, adult mice in which most peripheral CD4(+) or CD8(+) T cells lacked the receptor for TGF-β showed no signs of autoimmunity. Because of their enhanced responses to weak stimulation of the T cell antigen receptor, when transferred into lymphopenic recipients, naive TGF-β-unresponsive T cells underwent much more proliferation and differentiation into effector cells and induced lymphoproliferative disease. We propose that TGF-β signaling controls the self-reactivity of peripheral T cells but that in the absence of TGF-β signals, an added trigger such as lymphopenia is needed to drive overt autoimmune disease.
Department of Immunology and the Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
Nu
N
Zhang
Michael J
MJ
Bevan
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000276:immunology; D008297:Male; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse