Differential survival of γδT cells, αβT cells and NK cells upon engagement of NKG2D by NKG2DL-expressing leukemic cells.
Herein, we show that γδT, CD8(+) αβT lymphocytes and natural killer (NK) cells display a different sensitivity to survival signals delivered via NKG2D surface receptor. All the three effector cell populations activate Akt1/PKBalpha through the engagement of this molecule. Upon binding to leukemic cells expressing NKG2D ligands (NKG2DL), including chronic lymphocytic leukemias treated with transretinoic acid, most γδT (>60%) and half CD8(+) αβT cells (about 50%) received a survival signal, at variance with the majority of NK cells (>80%) that underwent apoptosis by day 5. Interestingly, oligomerization of NKG2D in γδT or CD8(+) αβT cells, led to a significant rise in nuclear/cytoplasmic ratio of both NF-kBp52 and RelB, the two NF-kB subunits mainly involved in the transcription of antiapoptotic proteins of the Bcl family. Indeed, the ratio between the antiapoptotic protein Bcl-2 or Bcl-x(L) and the proapoptotic protein Bax raised in γδT or CD8(+) αβT cells following NKG2D engagement by specific monoclonal antibodies or by NKG2DL expressing leukemic cells. Conversely, nuclear translocation of NF-kBp52 or RelB did not increase, nor the Bcl-2/Bax or the Bcl-x(L) /Bax ratios changed significantly, in NK cells upon oligomerizaton of NKG2D. Of note, transcripts for α5 importin, responsible for nuclear translocation of NF-kBp52/Rel B heterodimer, are significantly higher in γδT and CD8(+) αβT cells than in NK cells. These biochemical data may explain, at least in part, why γδT and CD8(+) αβT cells are cytolytic effector cells more resistant to target-induced apoptosis than NK cells.
Poggi
Alessandro
A
Unit of Molecular Oncology and Angiogenesis, National Institute for Cancer Research, I-16132 Genoa. alessandro.poggi@istge.it
Zancolli
Marta
M
Boero
Silvia
S
Catellani
Silvia
S
Musso
Alessandra
A
Zocchi
Maria Raffaella
MR
D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D007938:Leukemia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000502:physiology*
D055655:NK Cell Lectin-Like Receptor Subfamily K; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051057:Proto-Oncogene Proteins c-akt