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Differential Effects of Interleukin-2 and Interleukin-15 versus Interleukin-21 on CD4+ Cutaneous T-Cell Lymphoma Cells

Departments of ¹ Pathology and Laboratory Medicine, ² Dermatology, and ³ Biostatistics and ⁴ Penn Microarray Facility, University of Pennsylvania, Philadelphia, Pennsylvania and ⁵ Institute of Medical Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark

Requests for reprints: Mariusz A. Wasik, University of Pennsylvania Medical Center, Department of Pathology and Laboratory Medicine, 7.106 Founders, Philadelphia, PA 19104. Phone: 215-662-3467; Fax: 215-662-7529; E-mail: wasik{at}mail.med.upenn.edu.

Key Words: T cells • cytokines • interleukin-2 (IL-2) • interleukin-15 (IL-15) • interleukin-21 (IL-21)

In this study, we compared the effects of interleukin-2 (IL-2), IL-15, and IL-21 on gene expression, activation of cell signaling pathways, and functional properties of cells derived from CD4+ cutaneous T-cell lymphoma (CTCL). Whereas both IL-2 and IL-15 modulated, in a CTCL cell line, the expression of >1,000 gene transcripts by at least 2-fold, IL-21 up-regulated <40 genes. All three cytokines induced tyrosine phosphorylation of Jak1 and Jak3 in CTCL cell lines and native leukemic (Sezary) cells. However, only IL-2 and IL-15 strongly activated signal transducers and activators of transcription 5, phosphoinositide 3-kinase/Akt, and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK signaling pathways in the cell lines and mitogen-primed native cells. In contrast, IL-21 selectively activated signal transducers and activators of transcription 3. Whereas all three cytokines protected CTCL cells from apoptosis, only IL-2 and IL-15 promoted their proliferation. The effects of the cytokine stimulation were Jak3 kinase– and Jak1 kinase– dependent. These findings document the vastly different effect of IL-2 and IL-15 versus IL-21 on CTCL cells. They also suggest two novel therapeutic approaches to CTCL and, possibly, other CD4+ T-cell lymphomas: inhibition of the Jak1/Jak3 kinase complex and, given the known strong immunostimulatory properties of IL-21 on CD8+ T, natural killer, and B cells, application of this cytokine to boost an immune response against malignant CD4+ T cells. [Cancer Res 2008;68(4):1083–90]