CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch.
CTLA-4 (CD152) is a regulatory molecule in the immune system fundamentally important for the inhibition of T cell activity that is mediated by an unknown mechanism. Here we demonstrate similarities of CTLA-4 and Itch deficient mice and that CTLA-4 deficient T cells show a massive reduction in the overall ubiquitination of proteins. CTLA-4-mediated signal transduction leads to increased de-phosphorylation and therefore activation of the ubiquitin ligase Itch and enhanced ubiquitination of the Itch target molecule JunB. The knock-down of Itch completely abolishes the inhibitory effect of CTLA-4-mediated signal transduction on mRNA accumulation of IFN-gamma and IL-4. These results show that CTLA-4 mediates signals via the activation of the ubiquitin ligase Itch probably leading to the enhanced ubiquitination of Itch target molecules resulting in inhibition of T cell activity.
Hoff
Holger
H
Deutsches Rheuma-Forschungszentrum Berlin, 10117 Berlin, Germany. hoff@uni-mainz.de <hoff@uni-mainz.de>
Kolar
Paula
P
Ambach
Andreas
A
Radbruch
Andreas
A
Brunner-Weinzierl
Monika C
MC
D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D060908:CTLA-4 Antigen; D004789:Enzyme Activation / Q000276:immunology*; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases