Hsp72-mediated augmentation of MHC class I surface expression and endogenous antigen presentation.
Efficient recognition of tumor cells by cytolytic T lymphocytes (CTL) is often dependent on the presentation of cytosolic peptides in the context of MHC class I molecules. This process may be influenced by various molecular chaperones. To analyze this influence, we have utilized B16 melanoma cells, which are not effectively recognized by MHC class I-restricted CTL. This resistance to CTL is apparently due to a very low level of surface MHC expression. We have found that stably transfected clones of B16 which constitutively express the human heat shock protein 72 (Hsp72) exhibit significantly increased levels of MHC class I antigens on their surface. This Hsp72-mediated up-regulation of surface MHC class I antigen represents an increase in the amount of functional MHC-peptide complexes as measured by conformation-dependent antibodies and recognition by MHC class I-restricted CTL. Expression of Hsp72 did not improve the antigen presentation defect in cells lacking the activity of the transporter associated with antigen presentation (TAP). Moreover, mice immunized with Hsp72-expressing B16 cells, but not with control-transfected B16 cells, display significantly increased resistance to a subsequent challenge with live, wild-type B16. Together, our data demonstrate that the immune recognition of tumor cells can be substantially enhanced by the suitable expression of a molecular chaperone.
Wells
A D
AD
Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison 53706, USA.
Rai
S K
SK
Salvato
M S
MS
Band
H
H
Malkovsky
M
M
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D005260:Female; D015870:Gene Expression; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D011994:Recombinant Proteins