Institute for Medical Informatics and Biometry, Medical Faculty Carl Gustav Carus , Dresden , Germany.
Senckenberg Institute of Pathology, Goethe-University Hospital Frankfurt , Frankfurt , Germany.
Front Immunol. 2013 Nov 21;4:380. doi: 10.3389/fimmu.2013.00380. eCollection 2013.
T-cell receptor (TCR) polyclonal mature T cells are surprisingly resistant to oncogenic transformation after retroviral insertion of T-cell oncogenes. In a mouse model, it has been shown that mature T-cell lymphoma/leukemia (MTCLL) is not induced upon transplantation of mature, TCR polyclonal wild-type (WT) T cells, transduced with gammaretroviral vectors encoding potent T-cell oncogenes, into RAG1-deficient recipients. However, further studies demonstrated that quasi-monoclonal T cells treated with the same protocol readily induced MTCLL in the recipient mice. It has been hypothesized that in the TCR polyclonal situation, outgrowth of preleukemic cells and subsequent conversion to overt malignancy is suppressed through regulation of clonal abundances on a per-clone basis due to interactions between TCRs and self-peptide-MHC-complexes (spMHCs), while these mechanisms fail in the quasi-monoclonal situation. To quantitatively study this hypothesis, we applied a mathematical modeling approach. In particular, we developed a novel ordinary differential equation model of T-cell homeostasis, in which T-cell fate depends on spMHC-TCR-interaction-triggered stimulatory signals from antigen-presenting cells (APCs). Based on our mathematical modeling approach, we identified parameter configurations of our model, which consistently explain the observed phenomena. Our results suggest that the preleukemic cells are less competent than healthy competitor cells in acquiring survival stimuli from APCs, but that proliferation of these preleukemic cells is less dependent on survival stimuli from APCs. These predictions now call for experimental validation.
T 细胞受体 (TCR) 多克隆成熟 T 细胞在逆转录病毒插入 T 细胞癌基因后，对致癌转化具有惊人的抗性。在小鼠模型中，已经表明，在将成熟、TCR 多克隆野生型 (WT) T 细胞移植到缺乏 RAG1 的受体中，并转导编码有效 T 细胞癌基因的γ逆转录病毒载体后，不会诱导成熟 T 细胞淋巴瘤/白血病 (MTCLL)。然而，进一步的研究表明，用相同方案处理的准单克隆 T 细胞很容易在受体小鼠中诱导 MTCLL。有人假设，在 TCR 多克隆情况下，由于 TCR 与自身肽-MHC 复合物 (spMHC) 之间的相互作用，基于每个克隆调节克隆丰度，前白血病细胞的生长和随后向显性恶性肿瘤的转化受到抑制，而这些机制在准单克隆情况下失败。为了定量研究这一假设，我们应用了数学建模方法。特别是，我们开发了一种新的 T 细胞动态平衡的常微分方程模型，其中 T 细胞命运取决于抗原呈递细胞 (APC) 上 spMHC-TCR 相互作用触发的刺激信号。基于我们的数学建模方法，我们确定了模型的参数配置，这些配置一致地解释了观察到的现象。我们的结果表明，前白血病细胞从 APC 获得生存刺激的能力不如健康竞争细胞，但其增殖对来自 APC 的生存刺激的依赖性较小。这些预测现在需要实验验证。
