title: TCR-independent killing of B cell malignancies by anti-third-party CTLs: the critical role of MHC-CD8 engagement.
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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Lask
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Adva
authors.initials: A
authors.lastname: Cohen
authors.forename: Rinat
authors.initials: R
authors.lastname: Goren-Arbel
authors.forename: Oren
authors.initials: O
authors.lastname: Milstein
authors.forename: Shraga
authors.initials: S
authors.lastname: Aviner
authors.forename: Ilan
authors.initials: I
authors.lastname: Feine
authors.forename: Eran
authors.initials: E
authors.lastname: Ophir
authors.forename: Shlomit
authors.initials: S
authors.lastname: Reich-Zeliger
authors.forename: David
authors.initials: D
authors.lastname: Hagin
authors.forename: Tirza
authors.initials: T
authors.lastname: Klein
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Alain
authors.initials: A
authors.lastname: Berrebi
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology
chemical_list: D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1