Cytotoxic T lymphocytes carrying a pattern recognition protein Tag7 can detect evasive, HLA-negative but Hsp70-exposing tumor cells, thereby ensuring FasL/Fas-mediated contact killing.
Within the broad problem of host immune surveillance versus tumor immune evasion, a most intriguing question is how the cellular immunity can cope with cancerous cells that have gotten rid of the classical antigen-presenting machinery. One such option stems from (1) the fact that HLA loss is often attended with expression of Hsp70 on the tumor cell surface, and (2) our findings that human lymphocytes express a protein Tag7 (also known as PGRP-S) capable of tight and specific interaction with cognate Hsp70. Here we show that a subpopulation of human CD4(+)CD25(+) lymphocytes, obtained either in culture as lymphokine-activated killers or directly from healthy donors, carry Tag7 and FasL on their surface and can indeed kill the HLA-negative tumor-derived cells K562 and MOLT-4 that expose Hsp70 and Fas. The primary binding of lymphocyte Tag7 to target-cell Hsp70 is very specific (eg, it is blocked by preincubating either cell with minimal peptides from the "partner" protein), and secures cell contact indispensable for subsequent FasL/Fas-triggered apoptosis. Unrelated to natural killer cell action or the putative role of Hsp as an antigen-presenting substitute, this novel mechanism is rather a backup analog of orthodox (CD8(+)) target recognition (Tag7 acting as built-in T-cell receptor and Hsp70 itself as ligand).
Sashchenko
Lidia P
LP
Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia. sashchenko@genebiology.ru
Dukhanina
Elena A
EA
Shatalov
Yury V
YV
Yashin
Denis V
DV
Lukyanova
Tamara I
TI
Kabanova
Olga D
OD
Romanova
Elena A
EA
Khaidukov
Sergei V
SV
Galkin
Alexander V
AV
Gnuchev
Nikolai V
NV
Georgiev
Georgii P
GP
D017209:Apoptosis; D019921:Biotinylation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006680:HLA Antigens / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D020014:K562 Cells / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
D053222:Fas Ligand Protein; D006680:HLA Antigens; D018840:HSP70 Heat-Shock Proteins; D019014:fas Receptor