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Originally published online as doi:10.1189/jlb.0107073 on December 17, 2007

Published online before print December 17, 2007
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(Journal of Leukocyte Biology. 2008;83:589-601.)
© 2008 by Society for Leukocyte Biology

Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia

Marcin W. Wlodarski*,{dagger}, Zachary Nearman*, Anna Jankowska*, Nina Babel{dagger},§, Jennifer Powers*, Patrick Leahy{ddagger}, Hans-Dieter Volk{dagger} and Jaroslaw P. Maciejewski*,1

* Experimental Hematology and Hematopoiesis Section, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA;
{dagger} Institute of Medical Immunology, Charite Medical School, Berlin, Germany;
{ddagger} Gene Expression Array Core Facility, Case Western Reserve University, Cleveland, Ohio, USA; and
§ Department of Nephrology, Campus Virchow, Charite Medical School, Berlin, Germany

1Correspondence: Taussig Cancer Center/R40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. E-mail: marwlo{at}gmail.com

T cell large granular lymphocyte leukemia (T-LGL) is a chronic clonal lymphoproliferation of CTL. In many ways, T-LGL clones resemble terminal effector CTL, including down-modulation of CD28 and overexpression of perforin, granzymes, and CD57. We studied the transcriptome of T-LGL clones and compared it with healthy CD8+CD57+ effector cells as well as CD8+CD57– populations. T-LGL clones were sorted based on their TCR variable β-chain restriction, and controls were obtained by pooling cell populations from 14 donors. Here, we focus our analysis on immunological networks, as immune mechanisms play a prominent role in the etiology of bone marrow failure in T-LGL. Informative genes identified by expression arrays were studied further in an independent cohort of patients using Taqman PCR, ELISA assays, and FACS analysis. Despite a strikingly similar gene expression profile between T-LGL clones and their healthy counterparts, important phenotypic differences were identified, including up-modulation of TNFRS9, myeloid cell leukemia sequence 1, IFN-{gamma}, and IFN-{gamma}-related genes, and several integrins/adhesion molecules. In addition, T-LGL clones were characterized by an overexpression of chemokines and chemokine receptors that are typically associated with viral infections (CXCL2, Hepatitis A virus cellular receptor 1, IL-18, CCR2). Our studies suggest that immunodominant LGL clones, although phenotypically similar to effector CTL, show significantly altered expression of a number of genes, including those associated with an ongoing viral infection or chronic, antigen-driven immune response.

Key Words: autoimmune • antigen-driven • CTL expansion • viral infection