TCR-independent killing of B cell malignancies by anti-third-party CTLs: The critical role of MHC-CD8 engagement

Assaf Lask, Polina Goichberg, Adva Cohen, Rinat Goren-Arbel, Oren Milstein, Shraga Aviner, Ilan Feine, Eran Ophir, Shlomit Reich-Zeliger, David Hagin, Tirza Klein, Arnon Nagler, Alain Berrebi, Yair Reisner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2006-2014
Number of pages9
JournalJournal of Immunology
Volume187
Issue number4
DOIs
StatePublished - 15 Aug 2011
Externally publishedYes

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