Common clonal chromosome aberrations in cytokine-dependent continuous human T-lymphocyte cell lines

doi:10.1016/0165-4608(95)00118-2

Cancer Genetics and Cytogenetics

Volume 85, Issue 1, November 1995, Pages 68-71

https://doi.org/10.1016/0165-4608(95)00118-2 Get rights and content

Abstract

Antigen-mediated T-cell proliferation is a transient phenomenon. Like other somatic cells, T lymphocytes generally show replicative senescence in vitro. However, we here show that cytokine-dependent continuous (immortal) T-cell lines can be established from skin biopsy specimens of inflammatory skin diseases. Continuous growth can be obtained by culturing T cells in medium supplemented with interleukin-2 and interleukin-4, but without antigen or antigen-presenting cells added. Loss of the T-cell antigen receptor complex is observed in some of the continuous T-cell lines. Most T-cell lines develop clonal chromosome aberrations during continuous growth. Aberrations for chromosomes 1, 2, 8, 16, and 18 are most commonly observed.

References (10)

K. Kaltoft et al.
Cytogenetic findings in cell lines from cutaneous T cell lymphoma
Dermatol Clin
(1994)
N.L. Perillo et al.
Human T lymphocytes possess a limited in vitro life span
Exp Geront
(1989)
K. Kaltoft et al.
Appearance of isochromosome 18q can be associated with in vitro immortalization of human lymphocytes
Cancer Genet Cytogenet
(1995)
K. Kaltoft et al.
A continuous T cell line from a patient with Sezary syndrome
Arch Dermatol Res
(1987)
J.T. Abrams et al.
A clonal CD4-positive T cell line established from the blood of a patient with Sezary syndrome
J Invest Dermatol
(1991)

There are more references available in the full text version of this article.

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^☆: This work was supported by grants 93-025 and 93-026 from the Danish Cancer Society, and grant 12-1330 from the Danish Medical Research Council.

^∗∗: Hoffmann la Roche and Schering-Plough are thanked for their generous gift of IL-2 and IL-4, respectively. We thank T. Schneiderma for her invaluable advice.

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Original articleCommon clonal chromosome aberrations in cytokine-dependent continuous human T-lymphocyte cell lines☆

Abstract

Dermatol Clin

Exp Geront

Cancer Genet Cytogenet

A continuous T cell line from a patient with Sezary syndrome

Arch Dermatol Res

A clonal CD4-positive T cell line established from the blood of a patient with Sezary syndrome

J Invest Dermatol

Original article
Common clonal chromosome aberrations in cytokine-dependent continuous human T-lymphocyte cell lines☆