Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates
Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates
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DOI：
10.1006/jtbi.2000.2169
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发表时间：
2000-11-21
影响因子：
2
通讯作者：
Carneiro, J
中科院分区：
文献类型：
--
作者：
León, K;Peréz, R;Carneiro, J
对外周体抗原的耐受涉及多种机制，即T细胞介导的潜在自身免疫细胞的抑制。最近在体内和体外的证据表明，调节性T细胞抑制效应T细胞的反应的机制，需要同时结合的调节性和效应T细胞与相同的抗原呈递细胞（APC）。尽管有这种强烈的要求，但尚不清楚当两种细胞结合时会发生什么。在文献中讨论了几个假设。抑制可能是由于调节细胞和效应细胞对APC上的活化资源的简单竞争;调节性T细胞可以向同一缀合物中的效应T细胞递送抑制信号;或者效应T细胞可以在与调节性T细胞相互作用期间获得调节表型。本文试图进一步了解T细胞介导的抑制，并缩小候选机制的数量。我们提出了第一个一般形式主义描述的T细胞和APC的多细胞缀合物的形成。使用这种形式主义，我们得到三个特定的模型，代表T细胞介导的抑制的替代机制。对于每个模型，我们进行相平面和分叉分析，并确定其利弊方面的关系与大量的T细胞介导的抑制实验观察。我们认为，会计过继转移的耐受性的定量细节需要模型与调节细胞或效应细胞占主导地位的稳态的调节制度。从这个分析中，我们得出结论，T细胞介导的抑制的最合理的机制需要调节性T细胞积极抑制效应T细胞的生长，并且调节性T细胞群体的维持依赖于效应T细胞。调节性T细胞群可取决于效应T细胞产生的生长因子和/或效应细胞向调节性表型的连续分化。(C)北京大学出版社.
Tolerance to peripheral body antigens involves multiple mechanisms, namely T-cell-mediated suppression of potentially autoimmune cells. Recent in vivo and in vitro evidence indicates that regulatory T cells suppress the response of effector T cells by a mechanism that requires the simultaneous conjugation of regulatory and effector T cells with the same antigen-presenting cell(APC). Despite this strong requirement, it is not yet clear what happens while both cells are conjugated. Several hypotheses are discussed in the literature. Suppression may result from simple competition of regulatory and effector cells for activation resources on the APC; regulatory T cells may deliver an inhibitory signal to effector T cells in the same conjugate; or effector T cells may acquire the regulatory phenotype during their interaction with regulatory T cells. The present article tries to further our understanding of T-cell-mediated suppression, and to narrow-down the number of candidate mechanisms. We propose the first general formalism describing the formation of multicellular conjugates of T cells and APCs. Using this formalism we derive three particular models, representing alternative mechanisms of T-cell-mediated suppression. For each model, we make phase plane and bifurcation analysis, and identify their pros and cons in terms of the relationship with the large body of experimental observations on T-cell-mediated suppression. We argue that accounting for the quantitative details of adoptive transfers of tolerance requires models with bistable regimes in which either regulatory cells or effecters cells dominate the steady state. From this analysis, we conclude that the most plausible mechanism of T-cell-mediated suppression requires that regulatory T cells actively inhibit the growth of effector T cells, and that the maintenance of the population of regulatory T cells is dependent on the effector T cells. The regulatory T cell population may depend on a growth factor produced by effector T cells and/or on a continuous differentiation of effector cells to the regulatory phenotype. (C) 2000 Academic Press.