Response to self antigen imprints regulatory memory in tissues.
Response to self antigen imprints regulatory memory in tissues.
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DOI：
10.1038/nature10664
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发表时间：
2011-11-27
期刊：
影响因子：
64.8
通讯作者：
Abbas, Abul K.
中科院分区：
文献类型：
--
作者：
Rosenblum, Michael D.;Gratz, Iris K.;Paw, Jonathan S.;Lee, Karen;Marshak-Rothstein, Ann;Abbas, Abul K.
组织中的免疫稳态是通过针对组织特异性抗原的致病性 T 细胞反应与组织抑制这些反应的能力之间的微妙平衡来实现的。目前尚不清楚组织和免疫系统沟通以建立和维持免疫稳态的机制。临床证据表明，长期或反复暴露于组织内的自身抗原会导致病理性自身免疫反应减弱，这可能是减轻炎症损伤和保留功能的一种手段。许多人体器官特异性自身免疫性疾病的特征是疾病的最初表现是最严重的，随后的发作的严重程度和持续时间较轻。事实上，尽管组织自身抗原持续表达，这些疾病通常会自发消退。在抗原特异性免疫疗法（抗原-SIT）的实践中，过敏原或自身抗原被反复注射到皮肤中，每次连续暴露后炎症反应都会减弱。尽管这些发现表明组织在对抗原重复反应后获得了减弱自身免疫反应的能力，但这种情况发生的机制尚不清楚。在这里，我们发现，在外周组织中表达自身抗原后，胸腺来源的调节性 T 细胞 (Treg 细胞) 被激活、增殖并分化为更有效的抑制因子，从而介导器官特异性自身免疫的解决。炎症反应消退后，活化的 Treg 细胞会保留在靶组织中，并在抗原重新表达时减弱随后的自身免疫反应。因此，Treg 细胞的功能是向靶组织赋予“调节记忆”。这些发现为理解 Treg 细胞在外周组织中暴露于自身抗原时如何反应提供了一个框架，并提供了组织如何调节自身免疫的机制见解。
Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathologic autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression. In the practice of antigen-specific immunotherapy (antigen-SIT), allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure. Although these findings suggest that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (Treg cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity. After resolution of the inflammatory response, activated Treg cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, Treg cells function to confer ‘regulatory memory’ to the target tissue. These findings provide a framework for understanding how Treg cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity.
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