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First published online August 17, 2004
doi: 10.1242/10.1242/jcs.01288
Research Article |
1 National Centre for Biological Sciences, UAS-GKVK Campus, Bellary Road, Bangalore 560065, India
2 National Institute of Immunology, Aruna Asaf Ali Road, New Delhi 110067, India
* Authors for correspondence (e-mail: mayor{at}ncbs.res.in; satyajit{at}nii.res.in)
Accepted 22 April 2004
Antigen-presenting cells (APCs) are expected to present peptides from endocytosed proteins via major histocompatibility complex (MHC) class II (MHCII) molecules to T cells. However, a large proportion of peptides purified from MHCII molecules are derived from cytosolic self-proteins making the pathway of cytosolic peptide loading onto MHCII of critical relevance in the regulation of immune self-tolerance. We show that peptides derived from cytoplasmic proteins either introduced or expressed in the cytoplasm are first detectable as MHCII-peptide complexes in LAMP-1+ lysosomes, prior to their delivery to the cell surface. These peptide-MHC complexes are formed in a variety of APCs, including peritoneal macrophages, dendritic cells, and B cells, and are able to activate T cells. This process requires invariant chain (Ii)-dependent sorting of MHCII to the lysosome and the activity of the molecular chaperone H-2M. This pathway is independent of the ER resident peptide transporter complex TAP and does not take place by cross-presentation from neighbouring cells. In conjunction with our earlier results showing that these peptides are derived by cytosolic processing via the proteasome, these observations provide evidence for a ubiquitous route for peptide transport into the lysosome for the efficient presentation of endogenous and cytoplasmic proteins to CD4 T cells.
Key words: Antigen presentation, MHCII, Cytosolic processing, Dendritic cells
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