Dendritic cell specific deletion of OTUD7b protects mice from experimental cerebral malaria

Cerebral malaria (CM) is a severe life-threatening neurological complication of human malaria. Studies in murine experimental cerebral malaria (ECM) have shown that dendritic cells (DCs) prime CD8+ T cells, which migrate to the brain and cause disturbance of the blood-brain-barrier (BBB). The intrinsic mechanisms leading to DC survival permitting the development of CD8+ T cell-mediated immunopathology are yet incompletely understood. The pleiotropic cytokine TNF, which is highly expressed in both CM and ECM, regulates both cell survival and cell death depending on the ubiquitination status of signaling molecules. However, our molecular understanding of the highly dynamic processes of ubiquitination and deubiquitination is still fragmentary. Here, we newly identified that the ovarian tumor deubiquitinating enzyme 7b (OTUD7b) prevents TNF-induced apoptosis of DCs, thereby enabling efficient priming of pathogen-specific CD8+ T cells and development of ECM. Mechanistically, OTUD7b stabilizes TRAF2 in both human and murine DCs by preventing its K48-ubiquitination and proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, which mediates (i) activation of NF-kB and MAP kinases, (ii) production of IL-12, and (iii) expression of anti-apoptotic molecules cFLIP and Bcl-xL. Consequently, mice with DC-specific OTUD7b-deficiency were protected from ECM due to DC apoptosis and a failure to induce CD8+ T cell-mediated brain pathology, Taken together our study identifies OTUD7b as a molecular switch deciding on DC survival and death in both human and murine DC and qualifies it as a potential therapeutic target to manipulate DC responses.