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., 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. ISSN (print) 0390-6078

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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 B-CLL 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 alpha 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.

Item Type: Article
Additional Information: This work was supported by Special Trustees of the Middlesex Hospital, UCH and Royal Free & UCL Medical School and INTAS [grant number EU 2239].
Uncontrolled Keywords: b-cll, cd4-cytotoxicity, perforin, in-vitro, cytokine production, dendritic cells, effector-cells, ex-vivo, apoptosis, mechanism, responses, immunotherapy, concanamycin
Research Area: Allied health professions and studies
Faculty, School or Research Centre: Faculty of Health and Social Care Sciences (until 2013)
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Depositing User: Lucinda Lyon
Date Deposited: 04 Jul 2008
Last Modified: 28 Jun 2010 11:54
URI: http://eprints.kingston.ac.uk/id/eprint/1075

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