Induced Sézary syndrome PBMCs poorly express immune response genes up-regulated in stimulated memory T cells

Abstract

Background Dysfunctions in memory T cells contribute to various inflammatory autoimmune diseases and neoplasms. We hypothesize that investigating the differences of genetic profiles between resting and activated naïve and memory T cells may provide insight into the characterization of abnormal memory T cells in diseases, such as Sézary syndrome (SS), a neoplasm composed of CD4+ CD45RO+ cells. Objective We determined genes distinctively expressed between resting and activated naive and memory cells. Levels of up-regulated genes in resting and activated memory cells were measured in SS PBMCs, which were largely comprised of CD4+ CD45RO+ cells, to quantitatively assess how different Sézary cells were from memory cells. Methods We compared gene expression profiles using high density oligo-microarrays between resting and activated naïve and memory CD4+ T cells. Differentially expressed genes were confirmed by qRT-PCR and immunoblotting. Levels of genes up-regulated in activated and resting memory T cells were determined in SS PBMCs by qRT-PCR. Results Activated memory cells expressed greater numbers of immune-mediated genes involved in effector function compared to naïve cells in our microarray analysis and qRT-PCR. Nine out of 14 genes with enhanced levels in activated memory cells had reduced levels in SS PBMCs (p<0.05). Conclusions Activation of memory and naïve CD4+ T cells revealed a diverging gap in gene expression between these subsets, with memory cells expressing immune-related genes important for effector function. Many of these genes were markedly depressed in SS patients, implying Sézary cells are markedly impaired in mounting immune responses compared to memory cells.

Evolving Insights in the Pathogenesis and Therapy of Cutaneous T‐cell lymphoma (Mycosis Fungoides and Sezary Syndrome)

“…However, IL17A is not measurable in the serum (Krejsgaard et al , 2011), suggesting that this cytokine may play a role in MF, but not in SS. This is consistent with our results showing that SS peripheral blood cells do not express IL17A (Chong et al , 2010).…”

Transcriptome analysis of Sézary syndrome and lymphocytic-variant hypereosinophilic syndrome T cells reveals common and divergent genes

“…Biomarkers with reduced expression, such as STAT4 , are most useful when combined with other positively expressed biomarker genes [3, 19]. Reduced expression of cytokine genes was also observed in stimulated SS T cells compared to ND (Figure 1B), confirming functional defects of SS T cells observed in our previous findings [26, 27]. Furthermore, a global deficit of functional, activation-dependent gene expression was apparent in SS T cells, with reduced amplitude of inducible gene expression compared to ND T cells (Figure 2A).…”

“…While we detected a core group of 23 genes that were significantly induced in all three cell types, the amplitude of inducible gene expression was globally reduced in SS compared to ND. Hampered inducible cytokine expression in SS was consistent with prior reports [26, 27], but the globally reduced amplitude of altered gene expression in SS in response to PMA+A23187 stimulation suggests that signaling defects in SS may not be limited to the T cell receptor complex. Activated L-HES T cells often produce more IL-5 than similarly activated normal T cells [11, 28].…”

“…Peripheral blood mononuclear cells (PBMC) were isolated from whole blood, pheresis collars, or leucoreduction chambers by density centrifugation using Ficoll [56]. We previously published Affimetrix HG U133 Plus2 microarray profiles of CD45RO + (memory) and CD45RA + (naïve) CD4 + T cells from healthy donors ( n = 3 each) [26]. CD4 + CD45RO + T cells from SS patients ( n = 3) described in the present report were isolated at the same time, and using the same methods, as described by Chong, et al [26].…”

Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

“…TWIST1 is also an important suppressor of chronic Th1 inflammation [107,108], and ectopic expression of Twist1 reduced effector cytokine expression in both Th1-and Th2-polarized cells [108]. This feature of TWIST1 may contribute to poorly inducible cytokine gene expression observed in SS cells [22,109]. In addition, the mechanism of TWIST1 overexpression may vary between patients, resulting from promoter hypomethylation [110], or gain of chromosomal region 7p21.1 harboring the TWIST1 gene [111].…”