Investigating the mechanistic basis for dendritic cell-intrinsic AIMp1 regulation of dendritic cell maturation and anti-tumor immunity 4111

Abstract Description Dendritic cells (DC) are the only antigen presenting cell subset capable of both initiating adaptive immunity and driving downstream immune polarization. As such, the importance of DCs for anti-tumor immunity is paramount, but tumor-associated DCs are often dysfunctional and fail to induce effective immune responses. Therefore, gaining a greater understanding of DC-intrinsic functions that drive favorable tumor immunity is critical for developing more effective cancer immunotherapeutics. Recent work has implicated the function of an intracellular protein complex—called the multi-aminoacyl tRNA synthetase complex (mARS)—in regulating tumor immunity. Within DCs, a mARS subunit, called AIMp1, is dispensable for normal DC hematopoiesis but is required during DC maturation to facilitate effective anti-tumor immunity. We therefore investigated the specific DC-intrinsic signaling events mediated by AIMp1 within maturing DCs. Early in the maturation process, we found a novel protein-protein interaction between AIMp1 and NMNAT1, indicating AIMp1 may regulate cellular signaling via intracellular NAD(H) homeostasis. Additionally, nearly all AIMp1 molecules were bound within mARS in steady-state immature DCs. But after stimulation, a pool of soluble intracellular AIMp1 forms, suggesting AIMp1’s role in DC signaling is dynamically regulated during maturation. In conclusion, this work revealed a novel mechanistic and stage-specific role for AIMp1 as a positive regulator of DC maturation. Funding Sources NIH 5R01AI153326 Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)