PDF(Pubmed)
Abstract：
We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal \'specificity\' level, i.e., probability of binding any particular epitope, was shown to be inversely related to the number of self-antigens that the cells have to be tolerant to. Experiments have demonstrated that T lymphocytes also become more specific during negative selection in the thymus, because cells expressing the most crossreactive receptors have the highest likelihood of binding a self-antigen, and hence to be tolerized (i.e., deleted, anergized, or diverted into a regulatory T cell phenotype). Thus, there are two -not mutually exclusive- explanations for the exquisite specificity of T cells, one involving evolution and the other thymic selection. To better understand the impact of both, we extend a previously developed mathematical model by allowing for T cells with very different binding probabilities in the pre-selection repertoire. We confirm that negative selection tends to tolerize the most crossreactive clonotypes. As a result, the average level of specificity in the functional post-selection repertoire depends on the number of self-antigens, even if there is no evolutionary optimization of binding probabilities. However, the evolutionary optimal range of binding probabilities in the pre-selection repertoire also depends on the number of self-antigens. Species with more self antigens need more specific pre-selection repertoires to avoid excessive loss of T cells during thymic selection, and hence mount protective immune responses. We conclude that both evolution and negative selection are responsible for the high level of specificity of lymphocytes.
摘要：
我们以前认为，T和B淋巴细胞的抗原受体进化为足够特异性，以避免通过阴性选择大量克隆型缺失。他们的最佳“特异性”水平，即，结合任何特定表位的概率，被证明与细胞必须耐受的自身抗原的数量成反比。实验表明，在胸腺的阴性选择过程中，T淋巴细胞也变得更加特异性。因为表达最交叉反应性受体的细胞与自身抗原结合的可能性最高，并因此被容忍(即，已删除,通电，或转化为调节性T细胞表型)。因此，对于T细胞的精确特异性，有两种不相互排斥的解释，一个涉及进化，另一个涉及胸腺选择。为了更好地理解两者的影响，我们通过允许在预选库中具有非常不同的结合概率的T细胞来扩展先前开发的数学模型.我们证实，阴性选择倾向于容忍最交叉反应的克隆型。因此,功能后选择库的平均特异性水平取决于自身抗原的数量，即使没有结合概率的进化优化。然而,预选库中结合概率的进化最佳范围也取决于自身抗原的数量.具有更多自身抗原的物种需要更具体的预选择库，以避免在胸腺选择过程中T细胞的过度损失，从而引发保护性免疫反应。我们得出的结论是，进化和阴性选择都是淋巴细胞特异性高的原因。
