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

Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway
Cytotoxic CD4+ T cells in patients with B cell chronic lymphocytic leukemia kill via a perforin-mediated pathway
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.
0390-6078
435-443
Porakishvili, N.
6432cb43-92ce-4cce-95ed-ca90f43d5b30
Kardava, L.
d142f070-d6d7-41be-a0a9-370db79704da
Jewell, A. P.
58aa82fb-d672-42f0-9a70-9660e4412850
Yong, K.
01b5d56e-a451-41e3-9c8f-8491ae03fb5c
Glennie, M. J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Akbar, A.
98c0d1f6-d721-4ae9-9b77-5c9312eb6e2c
Lydyard, P. M.
73ac7b05-9fb6-4774-b4de-ed4eb8ab2e2b
Porakishvili, N.
6432cb43-92ce-4cce-95ed-ca90f43d5b30
Kardava, L.
d142f070-d6d7-41be-a0a9-370db79704da
Jewell, A. P.
58aa82fb-d672-42f0-9a70-9660e4412850
Yong, K.
01b5d56e-a451-41e3-9c8f-8491ae03fb5c
Glennie, M. J.
9f6f0eff-4560-48c2-80cd-0ec116110ded
Akbar, A.
98c0d1f6-d721-4ae9-9b77-5c9312eb6e2c
Lydyard, P. M.
73ac7b05-9fb6-4774-b4de-ed4eb8ab2e2b

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), 435-443.

Record type: Article

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.

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Published date: April 2004

Identifiers

Local EPrints ID: 26532
URI: http://eprints.soton.ac.uk/id/eprint/26532
ISSN: 0390-6078
PURE UUID: 7bf3abca-d1af-4c56-adb7-40833754fbdb

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Date deposited: 21 Apr 2006
Last modified: 22 Jul 2022 20:35

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Contributors

Author: N. Porakishvili
Author: L. Kardava
Author: A. P. Jewell
Author: K. Yong
Author: M. J. Glennie
Author: A. Akbar
Author: P. M. Lydyard

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