Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α dendritic cells.

Parekh VV, Pabbisetty SK, Wu L, Sebzda E, Martinez J, Zhang J, Van Kaer L
Proc Natl Acad Sci U S A. 2017 114 (31): E6371-E6380

PMID: 28716903 · PMCID: PMC5547642 · DOI:10.1073/pnas.1706504114

The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC-specific -deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8α DCs and in the capacity of these cells to cross-present cell corpse-associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called "Light-chain 3 (LC3)-associated phagocytosis" (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific -deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulation of CD8α DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes.

MeSH Terms (18)

Animals Antigen Presentation Autophagy Autophagy-Related Proteins CD8 Antigens CD8-Positive T-Lymphocytes Cells, Cultured Class III Phosphatidylinositol 3-Kinases Cross-Priming Cytokines Dendritic Cells Endocytosis Histocompatibility Antigens Class I Melanoma, Experimental Membrane Proteins Mice Mice, Knockout Phagocytosis

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