The pathway for MHCII-mediated presentation of endogenous proteins involves peptide transport to the endo-lysosomal compartment.
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.
National Centre for Biological Sciences, UAS-GKVK Campus, Bellary Road, Bangalore 560065, India.
Aadish
A
Dani
Ashutosh
A
Chaudhry
Paushali
P
Mukherjee
Deepa
D
Rajagopal
Sumeena
S
Bhatia
Anna
A
George
Vineeta
V
Bal
Satyajit
S
Rath
Satyajit
S
Mayor
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000276:immunology / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000276:immunology* / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C489628:H-2M antigen, mouse; D000949:Histocompatibility Antigens Class II; D051907:Lysosomal Membrane Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D010455:Peptides; C486171:Tap1 protein, mouse; C045084:invariant chain