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Cholesterol regulates the loading of foreign antigens onto MHC class II in dendritic cells
Author(s) -
Berger Adam Craig,
Roche Paul A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1067.7
Subject(s) - microbiology and biotechnology , antigen , chemistry , mhc class ii , antigen presentation , intracellular , biology , immune system , major histocompatibility complex , immunology , t cell
In immature DCs, MHCII resides in cholesterol‐rich intracellular lysosomal compartments. Upon activation, intracellular MHCII binds antigenic peptides and traffics to the plasma membrane. In this study, we have investigated the role of membrane cholesterol in MHCII transport through the use of the cholesterol transport inhibitor U18666A. Pretreatment of immature DCs with U18666A had no effect on the LPS‐induced expression of either the DC maturation marker CD40 or cellular levels of total MHCII and only a slight effect on CD86. However, U18666A treated DCs had a reduced capacity to stimulate naïve antigen‐specific T cells. Similar results were found using DCs from mice lacking NPC1, a protein involved in lysosomal cholesterol egress. Pretreatment of DCs with U18666A resulted in a 4‐fold reduction in the surface and cellular expression of MHCII‐peptide complexes in immature DCs and almost completely inhibited the LPS‐induced appearance of MHCII‐peptide at the plasma membrane of mature DCs. Microscopic analysis of U18666A treated DCs shows that MHCII‐peptide complexes are not found in cholesterol engorged lysosomal antigen processing compartments, suggesting that there are fewer compartments that are competent for antigen loading. We conclude that lysosomal cholesterol regulates MHCII‐peptide loading but not MHCII transport from lysosomes to the plasma membrane in DCs. This work is supported by the NCI.