Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway

Porakishvili, N., Kardava, L., Jewell, A.P., Yong, K.L., Glennie, M.J., Akbar, A. and Lydyard, P.M. 2004. Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway. Haematologica. 89 (4), pp. 435-443.

TitleCytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway
AuthorsPorakishvili, N., Kardava, L., Jewell, A.P., Yong, K.L., Glennie, M.J., Akbar, A. and Lydyard, P.M.
Abstract

Background and Objectives: B-cell chronic lymphocytic leukemia (B-CLL) is a clonal expansion of CD5+B cells that accumulate due to their uncontrolled growth and resistance

to apoptosis. We have previously shown that up to 50% of blood CD4+ T cells in BCLL patients have a cytotoxicity-related CD28-CD57+ phenotype and high content of both granzyme B and perforin (PF). In this study we investigate the cytotoxic potential of these cells against autologous B-CLL cells.

Design and Methods: Blood CD4+ or CD8+ T cells were positively isolated from B-CLL patients and cultured under a range of conditions with autologous purified B-CLL cells and with bispecific [anti-CD3 x anti-CD19] antibodies. Apoptosis of labeled B-CLL cells was assessed using the change of mitochondrial membrane potential with the fluorescent dye DiOC6 and confirmed by annexin V binding.

Results: There was time- and dose-dependent killing of B-CLL cells by both CD8+ and CD4+ T cells and this ranged from 6.6 - 68.0% for CD4+ cells and 6.4 - 57.8% for CD8+

cells. Almost complete inhibition by concanamycin A suggests that CD4+ T cells like CD8+ T cells induced apoptosis through a perforin-mediated pathway, but not via Fas/FasL (as indicated by lack of blocking with brefeldin A), tumor necrosis factor or TRAIL.

Interpretation and Conclusions: This study shows that blood CD4+PF+ T cells enriched in B-CLL patients, are able to kill autologous B-CLL cells ex vivo, through bispecific antibodies via a perforin mediated mechanism.

KeywordsB-CLL, CD4-cytotoxicity, perforin
JournalHaematologica
Journal citation89 (4), pp. 435-443
ISSN0390-6078
YearApr 2004
FilePorakishvili_Kardave_Jewell_Yong_Glennie_Akbar_Lydyard_2004_final.pdf
Web address (URL)http://www.haematologica.org/journal/2004/890435.pdf
Publication dates
PublishedApr 2004

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