Rebecca S. Hesterberg, Matthew S. Beatty, Ying Han, Mario R. Fernandez, Afua A. Akuffo, William E. Goodheart, Chunying Yang, Shiun Chang, Christelle M. Colin, Aileen Y. Alontaga, Jessica M. McDaniel, Adam W. Mailloux, Julia M. R. Billington, Lanzhu Yue, Shonagh Russell, Robert J. Gillies, Sang Y. Yun, Muhammad Ayaz, Nicholas J. Lawrence, Harshani R. Lawrence, Xue-Zhong Yu, Jianing Fu, Lancia N. Darville, John M. Koomen, Xiubao Ren, Jane Messina, Kun Jiang, Timothy J. Garrett, Anjali M. Rajadhyaksha, John L. Cleveland, Pearlie K. Epling-Burnette

Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only known molecular target for this drug class, where drug-induced ubiquitin-dependent degradation of "neo-substrates" such as IKAROS, AIOLOS, and CK1α accounts for their biological activity. Far less clear is whether these Cereblon E3 ligase modulating compounds disrupt the endogenous functions of CRBN. Strikingly, here we report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T-cells augments their central metabolism manifest as elevated bioenergetics, with supraphysiological levels of polyamines secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Importantly, treatment with Celeblon-modulatingcompounds similarly augments central metabolism of human CD8+T-cell. Notably, the metabolic control of CD8+ T-cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn deficient T-cells have augmented antigen-specific cytolytic activity versus melanoma tumor cells ex vivo and in vivo and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of activated CD8+ T-cells and this phenotype can be exploited by treatment with drugs.