Astrocytic lipid droplets contain MHCII and may act as cogs in the antigen presentation machinery.

Lipid droplets (LDs) are crucial for energy homeostasis, but are also involved in a wide spectrum of other cellular processes. Accumulating data identifies LDs as an important player in inflammation. However, the underlying mechanisms and the impact of LDs on neuroinflammation remain unclear. Here, we describe a novel function of LDs in human astrocytes, in the context of Alzheimer's disease (AD). Although, the overall lipid profile was unchanged in astrocytes with AD pathology, our data show a clear effect on LD metabolism and specific fatty acids involved in neuroinflammation. Importantly, we found astrocytes to be in close contact with infiltrating CD4 + T cells in the AD brain. Moreover, PLIN3 + LDs in astrocytes co-localize with major histocompatibility complex II (MHCII), indicating a role of LDs in adaptive immunity. Comprehensive analysis of human induced pluripotent stem cell (hiPSC)-derived astrocytes revealed that MHCII is in fact loaded within PLIN3 + LDs and forwarded to neighboring cells via tunneling nanotubes and secretion. Notably, the MHCII molecules are cleaved into its active form prior to packing, indicating an alternative route of MHCII shuttling through LDs, transporting functional immune complexes between cells. Quantification of PLIN3 + LDs in astrocytic cultures, human brain tissue and cerebral organoids indicates that AD pathology initially stimulates PLIN3 + LD formation, but in the long-run results in PLIN3 + LD consumption, which may have consequences on the astrocytes' MHCII distribution capacity. Taken together, our findings present a novel function of PLIN3 + LDs that can be of relevance for AD and other inflammatory conditions.