SEA Antagonizes the Imatinib-Meditated Inhibitory Effects on T Cell Activation via the TCR Signaling Pathway

Abstract

The BCR-ABL kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). However, long-term imatinib treatment induces immunosuppression, which is mainly due to T cell dysfunction. Imatinib can reduce TCR-triggered T cell activation by inhibiting the phosphorylation of tyrosine kinases such as Lck, ZAP70, LAT, and PLCγ1 early in the TCR signaling pathway. The purpose of this study was to investigate whether the superantigen SEA, a potent T cell stimulator, can block the immunosuppressive effects of imatinib on T cells. Our data show that the exposure of primary human T cells and Jurkat cells to SEA for 24 h leads to the upregulation of the Lck and ZAP70 proteins in a dose-dependent manner. T cells treated with SEA prior to TCR binding had increased the tyrosine phosphorylation of Lck, ZAP70, and PLCγ1. Pretreatment with SEA prevents the inhibitory effects of imatinib on TCR signaling, which leads to T cell proliferation and IL-2 production. It is conceivable that SEA antagonizes the imatinib-mediated inhibition of T cell activation and proliferation through the TCR signaling pathway.

T cell Receptor Vβ9 in Method for Rapidly Quantifying Active Staphylococcal Enterotoxin Type-A without Live Animals

“…In addition, unlike SEA, PHA cannot induce the secretion of IL-2 in CCRF-CEM T-cells with or without Raji B-cells as accessory cells as shown in Figure 6a. These results contrast to the findings of Wang et al [23] who reported that SEA alone in the absence of accessory cells could activate a T-cell clone.…”

“…Accessory cells are necessary for the reduction of TCR Vβ9 protein expression on CCRF-CEM T-cells using SEA but not using the plant lectin phytohemagglutinin (PHA). This is contrary to the findings of Wang et al [23] in which it was reported that SEA alone, without any co-stimulatory molecule, could elicit a response from a T-cell clone in the absence of any accessory cells that process SEA into antigenic peptides and present the fragmented SEA components via their major histocompatibility complexes (MHCs) to the T-cell. Our results in Figure 4 stand in contrast to that finding and reveal that the presence of Raji B-cells bearing co-stimulatory molecules are essential to generate a secondary cellular signal required for this effect.…”

“…While the mechanism of superantigenic activity is largely understood, there remains a recent dispute about the need for accessory cells to elicit a response from a T-cell clone by SEA. It is reported that SEA alone, without co-stimulatory molecule, can elicit a response from a T-cell clone in the absence of any accessory cells [23]. However, Kasper et al disputed this finding and reported that MHC class II molecules play a significant role in the immune response to bacterial superantigens [32].…”

CD8+ T cells are involved in early inflammation before macrophages in a rat adipose tissue engineering chamber model

“…The TEC model was used as the basis for the following experiments. All rats were divided into five groups ( n = 5 per group; Figure ): the control group, the zymosan A (Sigma‐Aldrich)‐treated group (0.1 mg, intraperitoneal injection to induce inflammation; Hartog, Cozijnsen, de Vrij, & Garssen, ), the 5‐aminoisoquinolinone hydrochloride (Sigma‐Aldrich)‐treated group (3 mg/kg, tail vein injection to reduce inflammation; Di Paola et al, ), the imatinib (Sigma‐Aldrich)‐treated group (50 mg/kg, tail vein injection to inhibit the proliferation of T cells; Cwynarski et al, ; Wang, Yan, Chen, Lin, & Li, ), and the CD8+ T cell‐injected group (1 ml of T cells isolated from the peripheral blood and administered via the tail vein).…”