Ackerman et al

Ackerman et al - 2005 Nature Publishing Group

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Access of soluble antigens to the endoplasmic reticulum can explain cross-presentation by dendritic cells Anne L Ackerman 1 , Christoph Kyritsis 2 , Robert Tampe ´ 2 & Peter Cresswell 1 In dendritic cells (DCs), peptides derived from internalized particulate substrates are efFciently cross-presented by major histocompatibility complex (MHC) class I molecules. Exogenous soluble antigens are also presented by DCs but with substantially lower efFciency. Here we show that particulate and soluble antigens use different transport pathways. Particulate antigens have been shown to access peripheral endoplasmic reticulum (ER)–like phagosomes that are competent for cross-presentation, whereas we show here that soluble proteins that escape proteolysis enter the lumen of the ER. ±rom there, they may be translocated into the cytosol by the pathway established for ER-associated degradation and their derived peptides may be transported back into the ER for binding by MHC class I molecules. MHC class I presentation involving the constitutive retrograde transport of soluble proteins to the ER by DCs may facilitate DC tolerance to components of their extracellular environment. Cytotoxic CD8 + T lymphocytes (CTLs) are crucial for immunological control of viral and intracellular pathogen infections. These T cells target infected cells through the recognition of surface major histo- compatibility complex (MHC) class I molecules bearing peptide antigens derived from endogenously expressed pathogen proteins. Before becoming competent effector cells, however, CTLs Frst must be primed against these antigens by dendritic cells (DCs). ±or pathogens that do not infect DCs 1 or that inhibit DC function 2 , DCs acquire exogenous antigens from infected cells and present peptides derived from them in association with MHC class I molecules to initiate adaptive immune responses. This process, called ‘cross- presentation’, provides internalized proteins access to cytosolic protea- somes and their derived peptides access to the MHC class I processing machinery, an endoplasmic reticulum (ER)–based oligomeric complex containing dimers of MHC class I heavy chain and b 2 -microglobulin ( b 2 M), the transporter associated with antigen processing (TAP), calreticulin, the thiol oxidoreductase ERp57 and tapasin 3 . The description of ER-mediated phagocytosis has suggested a pathway that explains both the intersection of exogenous molecules with the ER and the high efFciency of cross-presentation observed for phagocytosed antigens 4 . In DCs and macrophages, the ER functions as a membrane donor during phagocytosis, creating peripheral phago- somes by contributing membrane 5 . Thus, internalized antigens initi- ally enter a compartment that typically contains ER-based proteins.
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Ackerman et al - 2005 Nature Publishing Group

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