Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction

Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase CbI-b is upregulated in T cells after tolerizing signals. Loss of CbI-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of CbI-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of CbI-b resulted in exacerbated autoimmunity. Mechanistically, loss of CbI-b rescues reduced calcium mobilization of anergic T cells, which was attributed to CbI-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for CbI-b in the regulation of peripheral tolerance and anergy of T cells.