Commensal-specific T cells are flexible Barrier tissues, like the skin, are sites where noninvasive commensal microbes constantly interact with resident T cells. These encounters can result in commensal-specific T cell responses that promote, for example, host defense and tissue repair. Harrison et al. show that subsets of skin-resident commensal-specific interleukin-17A–producing CD4+ and CD8+ T cells have a dual nature: They coexpress transcription factors that direct antagonistic antimicrobial (type 17) and antiparasite and pro–tissue repair (type 2) programs. When skin is damaged, epithelial cell alarmins license type 17 T cells to turn on type 2 cytokines. Thus, commensal-specific type 17 T cells can direct antimicrobial activity under homeostatic conditions but rapidly turn on tissue repair in the context of injury. Science, this issue p. eaat6280 Skin-resident T cells co-opt tissue residency and cell-intrinsic flexibility to promote local immunity in response to injury. INTRODUCTION Barrier tissues are constitutive targets of environmental stressors and are home to a highly diverse microbiota. When the immune system encounters these noninvasive microbes, one possible result is the induction of cognate T cell responses that control various aspects of tissue function, including antimicrobial defense and tissue repair. Given the extraordinary number of antigens expressed by the microbiota, a substantial fraction of barrier tissue–resident T cells are expected to be commensal-specific, accumulating over time in response to successive exposure to new commensals. Because barrier tissues are defined by the constitutive coexistence of commensals and commensal-reactive lymphocytes, any understanding of tissue homeostasis, response to injury, and tissue-specific pathologies must occur in the context of this fundamental dialog. RATIONALE The skin serves as a primary interface with the environment and is consequently a constitutive target of environmental stressors mediated by physical damage or invasive pathogens. Tissue protection from these challenges relies on rapid and coordinated local responses tailored to both the microenvironment and the nature of the instigating injury. Our study explored whether commensal-specific T cells can act as tissue sentinels, allowing rapid adaptation to defined injuries, and how dysregulation of these responses may have pathogenic consequences. RESULTS Homeostatic encounters with commensal microbes promoted the induction of commensal-specific interleukin-17A (IL-17A)–producing T cells [CD4+ (TH17) and CD8+ (TC17)] that persisted as tissue-resident memory cells. Surprisingly, commensal-specific T cells were characterized by coexpression of classically antagonistic transcription factors (RORγt and GATA-3) that control the respective expression of type 17 and type 2 programs. Consequently, commensal-specific T cells displayed a hybrid chromatin landscape that underlies the coexpression of a broad type 2 transcriptome, including the type 2 effector cytokines IL-5 and IL-13. Notably, during homeostasis, RORγt+ T cells expressed type 2 cytokine mRNA without subsequent protein translation. By contrast, in the context of tissue challenges such as chitin injection or insect bites, commensal-specific RORγt+ T cells were able to produce type 2 cytokines (IL-5 and IL-13). The spontaneous release of type 2 cytokines by these cells was also observed in the context of local defects in immune regulation associated with impaired regulatory T cell function. Alarmins associated with tissue damage and inflammation, such as IL-1, IL-18, IL-25, and IL-33, were able to superimpose a type 2 effector program on both TC17 and TH17 cells in the context of T cell receptor engagement. Using an IL-17A fate-mapping strategy, we found that IL-17A–committed RORγt+ T cells and their IL-17A−RORγt+ counterparts both produced type 2 cytokines in response to tissue alarmins. Such cellular plasticity allows commensal-specific type 17 cells to promote IL-17A–mediated antimicrobial defense under homeostatic conditions, as well as tissue repair in an IL-13–dependent manner in the context of tissue injury. CONCLUSION Our work describes a tissue checkpoint that relies on the remarkable plasticity and adaptability of tissue-resident commensal-specific T cells. We propose that this feature may also have important implications in the etiology of tissue-specific inflammatory disorders. The extraordinary number of both commensal-derived antigens and T cells at barrier sites suggests that the ability of commensal-specific T cells to functionally adapt to injury may play a fundamental role in controlling tissue physiology. Poised type 2 immunity of commensal-specific T cells promotes rapid adaptation to tissue injury. Commensal-specific T cells produce IL-17A under homeostatic conditions for antimicrobial defense while harboring a poised type 2 transcriptome. Tissue injury licenses type 2 immune potential of commensal-specific type 17 T cells, thereby promoting tissue repair. Impaired immune regulation unleashes type 2 cytokine production from commensal-specific CD8+ TC17 cells. Barrier tissues are primary targets of environmental stressors and are home to the largest number of antigen-experienced lymphocytes in the body, including commensal-specific T cells. We found that skin-resident commensal-specific T cells harbor a paradoxical program characterized by a type 17 program associated with a poised type 2 state. Thus, in the context of injury and exposure to inflammatory mediators such as interleukin-18, these cells rapidly release type 2 cytokines, thereby acquiring contextual functions. Such acquisition of a type 2 effector program promotes tissue repair. Aberrant type 2 responses can also be unleashed in the context of local defects in immunoregulation. Thus, commensal-specific T cells co-opt tissue residency and cell-intrinsic flexibility as a means to promote both local immunity and tissue adaptation to injury.

中文翻译：

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共生特异性 T 细胞可塑性促进组织对损伤的快速适应

共生特异性 T 细胞是灵活的屏障组织，如皮肤，是无创共生微生物不断与驻留 T 细胞相互作用的部位。这些相遇会导致共生特异性 T 细胞反应，例如促进宿主防御和组织修复。哈里森等人。表明皮肤驻留的共生特异性产生白细胞介素 17A 的 CD4+ 和 CD8+ T 细胞的亚群具有双重性质：它们共同表达指导拮抗性抗菌素（17 型）和抗寄生虫和前组织修复（2 型）程序的转录因子。当皮肤受损时，上皮细胞警报会许可 17 型 T 细胞开启 2 型细胞因子。因此，共生特异性 17 型 T 细胞可以在稳态条件下指导抗菌活性，但在损伤的情况下迅速启动组织修复。科学，这个问题 p。eaat6280 皮肤驻留 T 细胞选择组织驻留和细胞内在灵活性，以促进局部免疫以应对损伤。介绍 屏障组织是环境压力源的组成目标，是高度多样化微生物群的家园。当免疫系统遇到这些非侵入性微生物时，一种可能的结果是诱导同源 T 细胞反应，控制组织功能的各个方面，包括抗菌防御和组织修复。鉴于微生物群表达的抗原数量非常多，预计大部分屏障组织驻留 T 细胞是共生特异性的，随着时间的推移而积累，以响应连续暴露于新的共生体。因为屏障组织是由共生细胞和共生反应性淋巴细胞的组成共存定义的，对组织稳态、对损伤的反应和组织特异性病理的任何理解都必须在这个基本对话的背景下发生。基本原理皮肤是与环境的主要界面，因此是由物理损伤或侵入性病原体介导的环境压力源的组成目标。针对这些挑战的组织保护依赖于针对微环境和引发损伤的性质量身定制的快速和协调的局部反应。我们的研究探讨了共生特异性 T 细胞是否可以充当组织哨兵，允许快速适应确定的损伤，以及这些反应的失调如何可能产生致病后果。结果 与共生微生物的稳态接触促进了产生共生特异性白细胞介素 17A (IL-17A) 的 T 细胞 [CD4+ (TH17) 和 CD8+ (TC17)] 的诱导，这些 T 细胞作为组织驻留记忆细胞持续存在。令人惊讶的是，共生特异性 T 细胞的特征是共表达经典拮抗转录因子（RORγt 和 GATA-3），这些因子控制 17 型和 2 型程序的各自表达。因此，共生特异性 T 细胞显示出混合染色质景观，这是广泛的 2 型转录组共表达的基础，包括 2 型效应细胞因子 IL-5 和 IL-13。值得注意的是，在稳态期间，R​​ORγt+ T 细胞表达 2 型细胞因子 mRNA，而没有随后的蛋白质翻译。相比之下，在诸如甲壳素注射或昆虫叮咬等组织挑战的情况下，共生特异性 RORγt+ T 细胞能够产生 2 型细胞因子（IL-5 和 IL-13）。在与调节性 T 细胞功能受损相关的免疫调节局部缺陷的背景下，也观察到这些细胞自发释放 2 型细胞因子。与组织损伤和炎症相关的警报素，如 IL-1、IL-18、IL-25 和 IL-33，能够在 T 细胞受体参与的背景下在 TC17 和 TH17 细胞上叠加 2 型效应程序. 使用 IL-17A 命运映射策略，我们发现 IL-17A 承诺的 RORγt+ T 细胞及其对应的 IL-17A-RORγt+ T 细胞均产生 2 型细胞因子以响应组织警报。这种细胞可塑性允许共生特异性 17 型细胞在稳态条件下促进 IL-17A 介导的抗菌防御，以及在组织损伤的情况下以 IL-13 依赖性方式进行组织修复。结论我们的工作描述了一个组织检查点，它依赖于组织驻留的共生特异性 T 细胞的显着可塑性和适应性。我们认为这一特征也可能对组织特异性炎症性疾病的病因学具有重要意义。屏障部位的共生源性抗原和 T 细胞数量惊人，这表明共生特异性 T 细胞在功能上适应损伤的能力可能在控制组织生理学方面发挥重要作用。共生特异性 T 细胞的稳定 2 型免疫促进对组织损伤的快速适应。共生特异性 T 细胞在稳态条件下产生 IL-17A 以进行抗菌防御，同时具有稳定的 2 型转录组。组织损伤许可共生特异性 17 型 T 细胞的 2 型免疫潜能，从而促进组织修复。免疫调节受损会释放共生特异性 CD8+ TC17 细胞产生 2 型细胞因子。屏障组织是环境压力源的主要目标，是体内最多数量的抗原经历淋巴细胞的家园，包括共生特异性 T 细胞。我们发现皮肤驻留的共生特异性 T 细胞具有一个矛盾的程序，其特征是与 2 型状态相关的 17 型程序。因此，在损伤和暴露于炎症介质如白细胞介素 18 的情况下，这些细胞会迅速释放 2 型细胞因子，从而获得上下文功能。2 型效应器程序的这种获得促进了组织修复。在免疫调节局部缺陷的情况下，也可以释放异常 2 型反应。因此，共生特异性 T 细胞选择组织驻留和细胞内在灵活性作为促进局部免疫和组织对损伤的适应的手段。