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CUTTING EDGE |
Sensitivity In Vitro and In Vivo
* Department of Immunology, Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut Health Center, Farmington, CT 06032;
Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329;
Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and
Biogen Idec, Cambridge, MA 02142
Mice deficient in the E3 ubiquitin ligase Cbl-b have CD28-independent T cells and develop autoimmunity. We previously reported that Cbl-b–/– CD4+CD25– T effector cells are resistant in vitro to the antiproliferative effects of CD4+CD25+ regulatory T cells and TGF-
. We have now asked whether the resistance noted in Cbl-b–/– T cells is restricted solely to TGF-’s antiproliferative effects, whether the TGF- resistance has in vivo relevance, and whether a defect can be identified in the TGF- signaling pathway. We now demonstrate the following: 1) in vitro, Cbl-b deficiency prevents the TGF--mediated induction of Foxp3+ functional regulatory T cells; 2) in vivo, Cbl-b–/– mice show a significantly enhanced response to a tumor that is strictly TGF- regulated; and 3) Cbl-b–/– T effector cells have defective TGF--mediated Smad2 phosphorylation. These studies are the first to document that the E3 ubiquitin ligase Cbl-b plays an integral role in T cell TGF- signaling, and that its absence results in multifunctional TGF--related defects that have important disease-related implications.
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