| First Author | Screpanti V | Year | 2001 |
| Journal | J Immunol | Volume | 167 |
| Issue | 4 | Pages | 2068-73 |
| PubMed ID | 11489989 | Mgi Jnum | J:109869 |
| Mgi Id | MGI:3630045 | Doi | 10.4049/jimmunol.167.4.2068 |
| Citation | Screpanti V, et al. (2001) A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. J Immunol 167(4):2068-73 |
| abstractText | NK cells provide a line of defense against tumors and virus-infected cells that have lost the expression of one or more MHC class I isoforms. Here, we investigate whether inhibitors of apoptosis can block the rejection of tumors mediated by NK cells, by introducing the long form of Fas-associated death domain-like IL-1beta-converting enzyme-associated inhibitory protein (FLIP(L)) and poxvirus cytokine response modifier A (CrmA) into the MHC class I-deficient T lymphoma cell line RMA-S. RMA-S cells do not normally express Fas in vitro, and it was previously postulated that the rejection of these tumors by NK cells is strictly perforin dependent. We show that perforin-deficient NK cells directly mediate Fas up-regulation on RMA-S cells and thereafter kill the cells in a Fas-dependent manner, and that RMA-S FLIP(L) and RMA-S CrmA are protected from such killing. When injected in immunocompetent recipients, RMA-S cells up-regulate Fas, rendering in vivo-passed mock-transduced cells sensitive to Fas-mediated apoptosis. Moreover, RMA-S FLIP(L) and RMA-S CrmA cells establish aggressive tumors, in contrast to RMA-S mock cells that are rejected. These results demonstrate that FLIP(L) and CrmA function as tumor progression factors by protecting MHC class I-deficient tumors from rejection mediated by NK cells. Moreover, our data indicate that death receptor-mediated apoptosis has a more prominent role in the clearance of NK-sensitive tumors than previously suggested. |
