Switching between tolerance and immunity: Do counter-acting gene networks dictate Langerhans cell function in the skin?
Switching between tolerance and immunity: Do counter-acting gene networks dictate Langerhans cell function in the skin?
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耐受性和免疫之间的切换：反作用基因网络是否决定皮肤中的朗格汉斯细胞功能？
DOI：
10.1002/bies.202100072
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Bennett CL
中科院分区：
文献类型：
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作者：
Bennett CL
免疫反应必须在皮肤等屏障部位进行仔细调节，以确保我们对感染做出反应，而不是对可能进入体内的日常无害的侮辱做出反应。朗格汉斯细胞（LC）是一种独特的抗原呈递细胞群，在皮肤的整个外表皮层形成连续的网络。[1]然而，尽管他们在19世纪世纪发现，以及从斑马鱼到小鼠和人的LC的显着保护，我们对LC在皮肤免疫平衡中所起作用的理解仍然不透明。这种不确定性部分源于LC可以从表皮迁移到引流淋巴结（LN）以启动幼稚T细胞的事实。[2]但树突状细胞（DC），真皮的专职抗原呈递细胞，足以激活T细胞对大多数皮肤感染的反应。这些和其他研究结果导致了近年来出现的主导概念，即LC可能对调节T细胞对皮肤中无害抗原的反应更重要。在这种情况下，挑战该领域的主要突出问题是：与真皮DC群体相比，LC生物学是什么有利于诱导T细胞耐受？在本期BioEssays中，Polak和Singh试图通过考虑表皮角质形成细胞内LC的独特束缚以及来自其中形成的细胞附着的信号来深入了解这个问题。[3]从他们以前使用原发性人LC的基因组和表观遗传学分析的工作中带来了独特的视角，[4]他们假设LC在“致耐受性”或“免疫原性”状态下的存在是由反作用基因调控模块决定的。这些与表皮中细胞接触的破坏通过共享的核心激活/成熟基因模块相关联。[3]这一假设的核心是干扰素调节因子（IRF）所起的关键作用，作者和其他人先前表明，干扰素调节因子在DC和LC的T细胞刺激特性中起关键作用。因此，他们证实，在健康皮肤中，与表皮接触的丧失导致IRF 4的上调，IRF 4充当维持致耐受性基因程序表达的主开关。他们进一步假设炎症和感染导致相关因子IRF 1的TNFα依赖性活化，IRF 1抵消IRF 4依赖性基因程序并接管LC的控制，LC现在在到达LN时擅长启动T细胞免疫。这一假设的令人兴奋的本质在于这样一个概念，
Immune responses must be carefully regulated at barrier sites such as the skin to ensure that we respond to infection, but not the daily innocuous insults that may enter the body. Langerhans cells (LC) are a unique population of antigen presenting cells that form a contiguous network throughout the outer epidermal layer of the skin.[1] However, despite their discovery in the 19th century, and the remarkable conservation of LC from zebrafish to mice and men, our understanding of the role LC play in the balance of skin immunity remains opaque. This ambiguity stems partly from the fact that LC can migrate out of the epidermis to draining lymph nodes (LN) to prime naïve T cells.[2] But dendritic cells (DC), the professional antigen presenting cells of the dermis, are sufficient to activate T cell responses to most cutaneous infections. These and other findings have led to the emergence of the dominant concept in recent years that LC may be more important for regulating T cell responses to harmless antigens in the skin. In this case, the major outstanding question challenging the field is: what is it about LC biology compared to dermal DC populations that favors the induction of T cell tolerance?In this issue of BioEssays, Polak and Singh have sought to provide insight into this question by considering the unique tethering of LC within epidermal keratinocytes, and the signals derived from the cellular attachments formed therein.[3] Bringing a unique perspective from their previous work using genomic and epigenetic analysis of primary human LC,[4] they hypothesize that the existence of LC in “tolerogenic” or “immunogenic” states is determined by counter-acting gene regulatory modules. These are linked to the disruption of cell contacts in the epidermis via a shared core activation/maturation gene module.[3] This hypothesis is centered on the proposed pivotal roles played by interferon regulatory factors (IRF), previously shown by the authors and others to play key roles in the T cell-stimulatory properties of DC and LC. Thus, they posit that in healthy skin loss of contact with the epidermis leads to upregulation of IRF4, which acts as a master switch to maintain expression of a tolerogenic gene program. They further hypothesize that inflammation and infection leads to the TNFα-dependent activation of the related factor, IRF1, which counteracts the IRF4-dependent gene program and takes over control of LC, which are now proficient at initiating T cell immunity upon arrival in the LN. The exciting nature of this hypothesis lies in the concept that