Invariant chain controls H2-M proteolysis in mouse splenocytes and dendritic cells.
The association of invariant (Ii) chain with major histocompatibility complex (MHC) class II dimers is required for proper antigen presentation to T cells by antigen-presenting cells. Mice lacking Ii chain have severe abnormalities in class II transport, T cell selection, and B cell maturation. We demonstrate here that H2-M, which is required for efficient class II antigenic peptide loading, is unexpectedly downregulated in splenocytes and mature dendritic cells (DCs) from Ii(-/-) mice. Downregulation reflects an increased rate of degradation in Ii(-/-) cells. Degradation apparently occurs within lysosomes, as it is prevented by cysteine protease inhibitors such as E64, but not by the proteasome inhibitor lactacystin. Thus, Ii chain may act as a lysosomal protease inhibitor in B cells and DCs, with its deletion contributing indirectly to the loss of H2-M.
Pierre
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P
Department of Cell Biology and Section of Immunobiology, Ludwig Institute for Cancer Research, Yale University School of Medicine, New Haven, CT 06520-8002, USA.
Shachar
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I
Matza
D
D
Gatti
E
E
Flavell
R A
RA
Mellman
I
I
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D011232:Chemical Precipitation; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D006681:HLA-D Antigens / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006207:Half-Life; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006868:Hydrolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D000944:Antigens, Differentiation, B-Lymphocyte; C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; C045084:invariant chain; D010450:Endopeptidases