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.
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