Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta 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 deficiency prevents the TGF-beta-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-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 Cbl-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.
Wohlfert
Elizabeth A
EA
Department of Immunology, Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut Health Center, Farmington, CT 06032, USA.
Gorelik
Leonid
L
Mittler
Robert
R
Flavell
Richard A
RA
Clark
Robert B
RB
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases