Zinkernagel R M, Ehl S, Aichele P, Oehen S, Kündig T, Hengartner H
Department of Pathology, University Hospital, Zürich, Switzerland.
Immunol Rev. 1997 Apr;156:199-209. doi: 10.1111/j.1600-065x.1997.tb00969.x.
This review summarises experimental evidence to illustrate that induction of immune reactivity depends upon antigen reaching and being available in lymphoid organs in a dose- and time-dependent manner. If antigen reaches lymph organs in a localised staggered manner and with a concentration gradient, a response is induced in the draining lymph node. Antigen-presenting cells are of critical importance to transport antigen from the periphery to local organised lymphoid tissue. If antigen is all over the lymphoid system, then it deletes all specific cells in the thymus or induces them within a few days; because of their limited life-span they then die off, leaving the repertoire depleted of this specificity. If antigen does not reach lymphoid organs it is ignored by immune cells. Once a response is induced, activated but not resting T cells will reach antigen outside lymphoid organs, whereas activated B cells differentiate into plasma cells in an inducing environment, mostly in lymphoid tissue including bone marrow, but also in chronic lymphoid-like infiltrations in peripheral organs. In immunopathology (when the infectious agent is known) or in autoimmunity (when the triggering infectious agent is not known or not recognised) lymphoid tissue may become organised close to the antigen (e.g. in organ-specific autoimmune diseases) and may thereby maintain an autoantigen-driven disease-causing immune response for a long time. The notion that native T cells get induced or silenced in the periphery may be questioned because induction can only occur in lymphoid organs providing anatomical structures where critical cell-cell interactions are properly guided and where, therefore, cells are likely to meet sufficiently frequently and in a critical milieu. Since overall immune reactivity critically depends upon the localisation of antigens in a dose- and time-dependent manner, it seems more likely-but this remains to be shown-that activated T cells may get exhausted in non-lymphoid peripheral tissues, whereas they are usually maintained in lymphoid organs. The critical role of antigen in regulating immune responses also has relevance for our understanding of immunological defence against epithelial and mesenchymal tumours, against many infectious diseases and for understanding autoimmunity and immunological memory. Collectively the data indicate that antigen, dependent upon localisation, dose and time, seems to be the simplest regulator of immune responses.
本综述总结了实验证据，以说明免疫反应性的诱导取决于抗原以剂量和时间依赖性方式到达淋巴器官并在其中可用。如果抗原以局部交错的方式并伴有浓度梯度到达淋巴器官，则会在引流淋巴结中诱导出反应。抗原呈递细胞对于将抗原从外周转运到局部有组织的淋巴组织至关重要。如果抗原遍布淋巴系统，那么它会在胸腺中清除所有特异性细胞或在几天内诱导它们；由于它们的寿命有限，随后它们会死亡，从而使该特异性的库减少。如果抗原未到达淋巴器官，免疫细胞会忽略它。一旦诱导出反应，活化而非静止的T细胞将在淋巴器官外接触抗原，而活化的B细胞在诱导环境中分化为浆细胞，主要是在包括骨髓在内的淋巴组织中，但也在外周器官的慢性淋巴样浸润中。在免疫病理学（当感染因子已知时）或自身免疫中（当触发感染因子未知或未被识别时），淋巴组织可能会在抗原附近形成组织（例如在器官特异性自身免疫疾病中），从而可能长期维持自身抗原驱动的致病免疫反应。天然T细胞在外周被诱导或沉默的观点可能受到质疑，因为诱导只能发生在提供解剖结构的淋巴器官中，在这些结构中关键的细胞间相互作用得到适当引导，因此细胞可能足够频繁地在关键环境中相遇。由于整体免疫反应性关键取决于抗原以剂量和时间依赖性方式的定位，似乎更有可能的是——但这仍有待证明——活化的T细胞可能在非淋巴外周组织中耗竭，而它们通常在淋巴器官中得以维持。抗原在调节免疫反应中的关键作用对于我们理解针对上皮和间充质肿瘤的免疫防御、许多传染病以及理解自身免疫和免疫记忆也具有相关性。总体而言，数据表明，取决于定位、剂量和时间，抗原似乎是免疫反应最简单的调节因子。
