Cereblon, a molecular target of lenalidomide (IMiDs), negatively regulates T cell activation (IRM7P.715)

Thalidomide analogs classified as immunomodulatory drugs (IMiDs) are rapidly emerging T-cell stimulants for the treatment of cancer. Cereblon, an E3-Ub ligase receptor with no known immune regulatory function, is the first identified target of IMiDs. The drug is hypothesized to have antagonistic properties by interfering with substrate recruitment to the thalidomide-binding domain in cereblon, and agonistic activity through an exposed ring that may recruit new proteins to the Ub complex. To explore this further at the molecular level, we studied immune regulation in cereblon deficient mice ( crbn-/- ), which exhibited an expanded white blood cell and neutrophil compartment, and higher numbers of peripheral and splenic lymphocytes. Mature crbn-/- T cells were capable of proliferation and IL-2 production following CD3 ligation in the absence of CD28 co-ligation. This positively associates with proximal phosphorylation events including pZap70, pAKT, pro-survival Bcl-XL and Bcl-2 protein expression, and corresponds with decreased pro-apoptotic proteins Bim, Bad, and Bax. Consistent with this data in a lethal graft-versus-host (GVHD) model, MHC-class I mismatched T cells from crbn-/- mice showed shortened post-transplant survival, greater weight-loss, and higher IFN-γ compared to transplanted wild-type T-cells. These data suggest that native targets of cereblon restrain the activation threshold of T-cells and that IMiD-associated blockade of cereblon leads to T-cell potentiation.