Restoration of MHC class I surface expression and endogenous antigen presentation by a molecular chaperone.
Presentation of cytosolic peptides in the context of major histocompatibility complex (MHC) class I antigen is crucial for immune recognition of virus-infected and malignant cells. This process, which is often defective in cancer cells, involves a series of cellular events which may be facilitated by heat shock proteins (molecular chaperones). To address the influence of chaperone function on the presentation of cytosolic peptides, we have utilized B16 melanoma cells (H-2b). These tumour cells are resistant to lysis by MHC class I-restricted cytotoxic T lymphocytes (CTL), due to a very low level of surface MHC expression. The authors found that stably transfected clones of B16 expressing a heterologous heat shock protein (Hsp65) exhibit significantly increased levels of MHC class I antigens on their surface, and are effectively lysed by alloreactive CTL. These MHC class I molecules can form functional MHC-peptide complexes which are recognized by virus-specific CTL. Moreover, mice immunized with Hsp65-expressing tumour cells, but not with control-transfected tumour cells, display a significantly increased resistance to a subsequent challenge with live, wild-type B16. Together, these results indicate that the suitable expression of a molecular chaperone can overcome a defect in MHC class I expression and antigen presentation, and suggest a novel approach to cancer immunotherapy.
Wells
A D
AD
University of Wisconsin Medical School, Department of Medical Microbiology, Madison, USA.
Rai
S K
SK
Salvato
M S
MS
Band
H
H
Malkovsky
M
M
D000818:Animals; D017951:Antigen Presentation; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology; D018834:Chaperonin 60; D018833:Chaperonins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D005260:Female; D006183:H-2 Antigens / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014407:Tumor Cells, Cultured
D001426:Bacterial Proteins; D018834:Chaperonin 60; D006183:H-2 Antigens; D008565:Membrane Proteins; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins