Diebner Hans H, Kirberg Jörg, Roeder Ingo
Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Institute for Medical Informatics and Biometry, Fetscherstrasse 74, D-01307 Dresden, Germany.
Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
J Theor Biol. 2016 Jan 21;389:88-100. doi: 10.1016/j.jtbi.2015.10.033. Epub 2015 Nov 6.
Here we present a mathematical model for the dynamics of oncogenesis control in mature T-cell populations within the blood and lymphatic system. T-cell homeostasis is maintained by clonal competition for trophic niches (survival signals stimulated through interactions with self-antigens bound to major histocompatibility molecules), where a clone is defined as the set of T cells carrying the same antigen specific T-cell receptor (TCR). We analytically derive fitness functions of healthy and leukemic clone variants, respectively, that capture the dependency of the stability of the healthy T-cell pool against leukemic invaders on clonal diversity and kinetic parameters. Similar to the stability of ecosystems with high biodiversity, leukemic mutants are suppressed within polyclonal T-cell populations, i.e., in the presence of a huge number of different TCRs. To the contrary, for a low clonal diversity the leukemic clone variants are able to invade the healthy T-cell pool. The model, therefore, describes the experimentally observed phenomenon that preleukemic clone variants prevail in quasi-monoclonal experimental settings (in mice), whereas in polyclonal settings the healthy TCR variants are able to suppress the outgrowth of tumours. Between the two extremal situations of mono- and polyclonality there exists a range of coexistence of healthy and oncogenic clone variants with moderate fitness (stability) each. A variation of cell cycle times considerably changes the dynamics within this coexistence region. Faster proliferating variants increase their chance to dominate. Finally, a simplified niche variation scheme illustrates a possible mechanism to increase clonal T-cell diversity given a small niche diversity.
在此，我们提出了一个关于血液和淋巴系统中成熟T细胞群体肿瘤发生控制动力学的数学模型。T细胞稳态通过对营养小生境的克隆竞争来维持（通过与结合到主要组织相容性分子上的自身抗原相互作用刺激产生的存活信号），其中克隆被定义为携带相同抗原特异性T细胞受体（TCR）的T细胞集合。我们分别解析推导了健康克隆变体和白血病克隆变体的适应度函数，这些函数捕捉了健康T细胞库对白血病入侵者稳定性的依赖性，该依赖性取决于克隆多样性和动力学参数。与具有高生物多样性的生态系统的稳定性类似，白血病突变体在多克隆T细胞群体中受到抑制，即在存在大量不同TCR的情况下。相反，对于低克隆多样性，白血病克隆变体能够侵入健康T细胞库。因此，该模型描述了实验观察到的现象：白血病前期克隆变体在准单克隆实验环境（在小鼠中）中占主导，而在多克隆环境中健康TCR变体能够抑制肿瘤的生长。在单克隆性和多克隆性这两种极端情况之间，存在健康克隆变体和致癌克隆变体以适度适应度（稳定性）共存的范围。细胞周期时间的变化会显著改变这个共存区域内的动力学。增殖较快的变体增加了其占主导的机会。最后，一个简化的小生境变化方案说明了在小生境多样性较小的情况下增加克隆T细胞多样性的一种可能机制。
