Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions.
E3 ubiquitin ligases have been placed among the essential molecules involved in the regulation of T cell functions and T cell tolerance. However, it has never been experimentally proven in vivo whether these functions indeed depend on the catalytic E3 ligase activity. The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo. Thus, modulation of the E3 ligase activity of Cbl-b might be a novel modality to control T cell immunity in vaccination, cancer biology, or autoimmunity.
Institute of Molecular Biotechnology of the Austrian Academy of Science, A-1030 Vienna, Austria.
Magdalena
M
Paolino
Christine B F
CB
Thien
Thomas
T
Gruber
Reinhard
R
Hinterleitner
Gottfried
G
Baier
Wallace Y
WY
Langdon
Josef M
JM
Penninger
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D017635:Clonal Anergy / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D055879:Gene Knock-In Techniques; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017354:Point Mutation; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D054829:RING Finger Domains / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases