León K, Peréz R, Lage A, Carneiro J
Centro de Immunología Molecular, Habana, 11600, Cuba.
J Theor Biol. 2000 Nov 21;207(2):231-54. doi: 10.1006/jtbi.2000.2169.
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 effectors 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.
对周围身体抗原的耐受性涉及多种机制，即T细胞介导的对潜在自身免疫细胞的抑制。最近的体内和体外证据表明，调节性T细胞通过一种需要调节性T细胞和效应性T细胞与同一抗原呈递细胞（APC）同时结合的机制来抑制效应性T细胞的反应。尽管有这种强烈的要求，但目前尚不清楚当两种细胞结合时会发生什么。文献中讨论了几种假说。抑制可能源于调节性细胞和效应性细胞对APC上激活资源的简单竞争；调节性T细胞可能在同一结合物中向效应性T细胞传递抑制信号；或者效应性T细胞在与调节性T细胞相互作用期间可能获得调节性表型。本文试图增进我们对T细胞介导的抑制的理解，并缩小候选机制的数量。我们提出了第一个描述T细胞和APC多细胞结合物形成的一般形式。使用这种形式，我们推导了三个特定模型，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岔分析，并根据与大量关于T细胞介导的抑制的实验观察结果的关系，确定它们的优缺点。我们认为，考虑耐受性过继转移的定量细节需要具有双稳态的模型，其中调节性细胞或效应性细胞在稳态中占主导地位。从这个分析中，我们得出结论，T细胞介导的抑制最合理的机制要求调节性T细胞积极抑制效应性T细胞的生长，并且调节性T细胞群体的维持依赖于效应性T细胞。调节性T细胞群体可能依赖于效应性T细胞产生的生长因子和/或效应性细胞向调节性表型的持续分化。
