Cutting edge:: Deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-β sensitivity in vitro and in vivo

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-beta. We have now asked whether the resistance noted in Cbl-b(-/-) T cells is restricted solely to TGF-beta's antiproliferative effects, whether the TGF-beta resistance has in vivo relevance, and whether a defect can be identified in the TGF-beta signaling pathway. We now demonstrate the following: 1) in vitro, Cbl-b dificiency prevents the TGF-beta-mediated induction of Foxp(3+) functional regulatory T cells; 2) in vivo, Cbl-b(-/-) mice show a significantly enhanced response to a tumor that is strictly TGF-beta regulated; and 3) Cbl-b(-/-) T effector cells have defective TGF-beta-mediated Smad2 phosphorylation. These studies are the first to document that the E3 ubiquitin ligase Chl-b plays an integral role in T cell TGF-beta signaling, and that its absence results in multifunctional TGF-beta-related defects that have important disease-related implications.