Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease.
Targeted mutation of TGFbeta1 in mice demonstrated that TGFbeta1 is one of the key negative regulators of immune homeostasis, as its absence leads to activation of a self-targeted immune response. Nevertheless, because of the highly pleiotropic properties of TGFbeta and the presence of TGFbeta receptors on most cell types, its biologic role in the regulation of immune homeostasis is not yet understood. To limit the consequences of TGFbeta effects to a single cell type, we developed a transgenic approach to abrogate the TGFbeta response in key immune cells. Specifically, we expressed a dominant-negative TGFbeta receptor type II under a T cell-specific promoter and created a mouse model where signaling by TGFbeta is blocked specifically in T cells. Using this transgenic model, we show that T cell homeostasis requires TGFbeta signaling in T cells.
Gorelik
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Section of Immunobiology, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Flavell
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RA
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D015704:CD4 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II