Article ; Online: TCR-independent killing of B cell malignancies by anti-third-party CTLs: the critical role of MHC-CD8 engagement.
Journal of immunology (Baltimore, Md. : 1950)
2011 Volume 187, Issue 4, Page(s) 2006–2014
Abstract: ... of graft-versus-host reactivity and can eradicate B cell chronic lymphocytic leukemia cells in vitro or ... third-party CTLs can also efficiently eradicate primary non-Hodgkin B cell lymphoma by inducing slow apoptosis ... B cells. ...
| Abstract | We previously demonstrated that anti-third-party CTLs (stimulated under IL-2 deprivation against cells with an MHC class I [MHC-I] background different from that of the host and the donor) are depleted of graft-versus-host reactivity and can eradicate B cell chronic lymphocytic leukemia cells in vitro or in an HU/SCID mouse model. We demonstrated in the current study that human allogeneic or autologous anti-third-party CTLs can also efficiently eradicate primary non-Hodgkin B cell lymphoma by inducing slow apoptosis of the pathological cells. Using MHC-I mutant cell line as target cells, which are unrecognizable by the CTL TCR, we demonstrated directly that this killing is TCR independent. Strikingly, this unique TCR-independent killing is induced through lymphoma MHC-I engagement. We further showed that this killing mechanism begins with durable conjugate formation between the CTLs and the tumor cells, through rapid binding of tumor ICAM-1 to the CTL LFA-1 molecule. This conjugation is followed by a slower second step of MHC-I-dependent apoptosis, requiring the binding of the MHC-I α2/3 C region on tumor cells to the CTL CD8 molecule for killing to ensue. By comparing CTL-mediated killing of Daudi lymphoma cells (lacking surface MHC-I expression) to Daudi cells with reconstituted surface MHC-I, we demonstrated directly for the first time to our knowledge, in vitro and in vivo, a novel role for MHC-I in the induction of lymphoma cell apoptosis by CTLs. Additionally, by using different knockout and transgenic strains, we further showed that mouse anti-third-party CTLs also kill lymphoma cells using similar unique TCR-independence mechanism as human CTLs, while sparing normal naive B cells. |
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| MeSH term(s) | Animals ; Apoptosis/genetics ; Apoptosis/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; CD8 Antigens/genetics ; CD8 Antigens/immunology ; Cell Line, Tumor ; Female ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Humans ; Immunity, Cellular ; Intercellular Adhesion Molecule-1/genetics ; Intercellular Adhesion Molecule-1/immunology ; Lymphocyte Function-Associated Antigen-1/genetics ; Lymphocyte Function-Associated Antigen-1/immunology ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/immunology ; Lymphoma, B-Cell/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mice, SCID ; Mutation ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/pathology |
| Chemical Substances | CD8 Antigens ; Histocompatibility Antigens Class I ; Lymphocyte Function-Associated Antigen-1 ; Intercellular Adhesion Molecule-1 (126547-89-5) |
| Language | English |
| Publishing date | 2011-08-15 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 3056-9 |
| ISSN | 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381 |
| ISSN (online) | 1550-6606 |
| ISSN | 0022-1767 ; 1048-3233 ; 1047-7381 |
| DOI | 10.4049/jimmunol.1100095 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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