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

Abstract

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-γ, and IFN-γ-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.

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

“…These data are consistent with previous studies, which have demonstrated increased levels of IFN-g stimulated gene products, such as IP-10 and MIG, in the plasma of patients with LGL expansions unrelated to dasatinib treatment. 25 There were no significant differences between groups for any of the other 21 soluble factors measured in plasma. Thus, the cytokine perturbations in patients with dasatinib-associated LGL expansions are restricted and may reflect virus-specific responses dominated by IFN-g rather than general immune activation.…”

T-cell and natural killer-cell large granular lymphocyte leukemia neoplasias

“…23,96 In particular, T-LGL clones overexpressed chemokines and chemokine receptors that are usually associated with viral infections such as CXCL2, CCR2, and interleukin-18 (IL-18). 96,97 Sera from ~21% of patients with T-cell LGL were found to be reactive from a human T-cell leukemia virus I (HTLV-I) enzyme-linked immunosorbent assay (ELISA), compared to only 0.17% of normal controls. 98 Indeed, a few patients have been infected with HTLV-II, but most patients with LGL leukemia are not infected with prototypical HTLV I/II.…”

Molecular evidence for repertoire skewing of T large granular lymphocyte proliferation after allogeneic hematopoietic SCT: report of two cases

“…This scenario is reminiscent of T-LGL leukemia, where the emergence of the clonal cytotoxic T cell expansion is thought to be a consequence of a nonrandom, Ag-driven process. 6,7 Along these lines, the finding of repertoire restrictions and similarities (that is, high frequency of the TRBV6-5 gene) in both cases reported here supports a dynamic process of cytotoxic T cell responses against auto-and exo-Ags as the initial event in T-LGL lymphoproliferation. LGL populations with repertoire skewing detected by flow cytometry; (c, f ) dominant TRBV-TRBD-TRBJ clonotypes after EBV and CMV infection in the two cases follow a different temporal dynamics.…”