期刊
JOURNAL OF NEUROSCIENCE
卷 35, 期 6, 页码 2674-2688出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4389-14.2015
关键词
antigen presentation; endocytic trafficking; luminal contents; lysosome; microglia; size-based sorting
资金
- Major State Basic Research Program of China [2011CB504400]
- National Natural Science Foundation of China [31190060, 31490590, 91232000, 81221003, 31471308]
- National Key Technology R&D Program of the ministry of Science and Technology of China [2012BAI01B08]
- Program for Introducing Talents in Discipline to Universities
- Zhejiang Provincial Natural Science Foundation of China [Y2110057]
- Fundamental Research Funds for the Central Universities [2014FZA7007]
Microglia are the resident immune cells in the CNS and play diverse roles in the maintenance of CNS homeostasis. Recent studies have shown that microglia continually survey the CNS microenvironment and scavenge cell debris and aberrant proteins by phagocytosis and pinocytosis, and that reactive microglia are capable to present antigens to T cells and initiate immune responses. However, how microglia process the endocytosed contents and evoke an immune response remain unclear. Here we report that a size-dependent selective transport of small soluble contents from the pinosomal lumen into lysosomes is critical for the antigen processing in microglia. Using fluorescent probes and water-soluble magnetic nanobeads of defined sizes, we showed in cultured rodent microglia, and in a cell-free reconstructed system that pinocytosed proteins become degraded immediately following pinocytosis and the resulting peptides are selectively delivered to major histocompatibility complex class II (MHC-II) containing lysosomes, whereas undegraded proteins are retained in the pinosomal lumen. This early size-based sorting of pinosomal contents relied on the formation of transient tunnel between pinosomes and lysosomes in a Rab7- and dynamin II-dependent manner, which allowed the small contents to pass through but restricted large ones. Inhibition of the size-based sorting markedly reduced proliferation and cytokine release of cocultured CD4(+) T cells, indicating that the size-based sorting is required for efficient antigen presentation by microglial cells. Together, these findings reveal a novel early sorting mechanism for pinosomal luminal contents in microglial cells, which may explain how microglia efficiently process protein antigens and evoke an immune response.
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