Abstract

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex is a key player in macroautophagy/autophagy and MAP1LC3/LC3-associated phagocytosis (LAP), both of which play critical roles in mediating dendritic cell (DC) function. In this study, we assessed the contribution of PIK3C3 to DC function in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We found that Pik3c3-deficient DCs exhibited attenuated ability in reactivating encephalitogenic T cells in the central nervous system, leading to reduced incidence and severity of EAE in DC-specific Pik3c3-deficient mice. Additionally, animals with DC-specific deficiency of Rb1cc1 (essential for autophagosome nucleation but not LAP) but not Rubcn (required for LAP but not autophagy) were protected against EAE, suggesting that the EAE phenotype of DC-specific Pik3c3-deficient mice is associated with the lack of canonical autophagy rather than LAP. Collectively, our studies have revealed a critical role of PIK3C3 in DC function and in the pathogenicity of these cells during EAE. Our findings also have important implications for the development of immunotherapies to treat autoimmune diseases such as MS by targeting PIK3C3-containing complexes.

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